**Possible Contribution of the Basal Ganglia Brainstem System to the Pathogenesis of Parkinson's Disease**

Kaoru Takakusaki1, Kazuhiro Obara1 and Toshikatsu Okumura2 *1Research Center for Brain Function and Medical Engineering, 2Department of General Medicine, Asahikawa Medical University, School of Medicine, Japan* 

### **1. Introduction**

432 Etiology and Pathophysiology of Parkinson's Disease

Onali, P.; Olianas, M.C. and Gessa, G.L. (1985). Characterization of dopamine receptors

Parent, A. & Hazrati, L.N. (1995). Functional anatomy of the basal ganglia. II. The place of

Pollak, P.; Benabid, A.L.; Gervason, C.L.; Hoffmann, D.; Seigneuret, E. & Perret, J. (1993).

Sibley, D.R. & Monsma, F.J. Jr. (1992). Molecular biology of dopamine receptors. *Trends in pharmacological sciences*, Vol.13, No.2, (February 1992), pp. 61-9, ISSN 0165-6147 Smith, Y. & Parent, A. (1988). Neurons of the subthalamic nucleus in primates display

Smith, Y.; Hazrati, L.N. & Parent, A. (1990). Efferent projections of the subthalamic nucleus

Smith, Y.; Bevan, M.D.; Shink, E. & Bolam, J.P. (1998). Microcircuitry of the direct and

Svenningsson, P. & Le Moine, C. (2002). Dopamine D1/5 receptor stimulation induces c-fos

Tofighy, A.; Abbott, A.; Centonze, D.; Cooper, A.J.; Noor, E.; Pearce, S.M.; Puntis, M.;

*Brain research,* Vol.607, No.1-2, (April 1993), pp. 270-4, ISSN 0006-8993 Wamsley, J.K.; Gehrelt, D.R.; Filloux, F.M. & Dawson, T.M. (1989). Comparison of the

*neuroanatomy*, Vol.2, No.3, (May-June 1989), pp. 119-37, ISSN 0891-0618 Wechsler, L.R.; Savaki, H.E. & Sokoloff, L. (1979). Effects of D-and L-amphetamine on local

Zhu, Z.; Bartol, M.; Shen, K. & Johnson, S.W. (2002a). Excitatory effects of dopamine on

Zhu, Z.T.; Shen, K.Z. & Johnson, S.W. (2002b). Pharmacological identification of inward

*Neuropharmacology,* Vol.42, No.6, (May 2002), pp. 772-81, ISSN 0028-3908

No.1, (January 1979), pp. 15-22, ISSN 0022-3042

Vol.28, No.2, (August 1985), pp. 138-45, ISSN 0026-895X

13, ISSN 0091-3952

9967

0953-816X

40, ISSN 0006-8993

1988), pp. 353-6, ISSN 0006-8993

pp. 353-87, ISSN 0306-4522

*reviews,* Vol.20, No.1, (January 1995), pp. 128-54, ISSN 0165-0173

mediating inhibition of adenylatecyclase in rat striatum. *Molecular pharmacology*,

subthalamic nucleus and external pallidum in basal ganglia circuitry. *Brain research* 

Long-term effects of chronic stimulation of the ventral intermediate thalamic nucleus in different types of tremor. *Advances in neurology,* Vol.60, (1993), pp. 408-

glutamate but not GABA immunoreactivity. *Brain research,* Vol.453, No.1-2, (June

in the squirrel monkey as studied by the PHA-L anterograde tracing method. *The Journal of comparative neurology,* Vol.294, No.2, (April 1990), pp. 306-23, ISSN 0021-

indirect pathways of the basal ganglia. *Neuroscience,* Vol.86, No.2, (September 1998),

expression in the subthalamic nucleus: possible involvement of local D5 receptors. *The European journal of neuroscience*, Vol.15, No.1, (January 2002), pp. 133-42, ISSN

Stanford, I.M.; Wigmore, M.A. & Lacey, M.G. (2003). Excitation by dopamine of rat subthalamic nucleus neurones in vitro – a direct action with unconventional pharmacology. *Neuroscience*, Vol.116, No.1, (2003), pp. 157-66, ISSN 0306-4522 Trugman, J.M. and James, C.L. (1993). D1 dopamine agonist and antagonist effects on

regional cerebral glucose utilization in rats with intact dopaminergic innervation.

distribution of D1 and D2 dopamine receptors in the rat brain. *Journal of chemical* 

cerebral glucose utilization in the conscious rat. *Journal of neurochemistry,* Vol.32,

subthalamic nucleus neurones: in vitro study of rats pretreated with 6 hydroxydopamine and levodopa. *Brain Research,* Vol.945, No.1, (July 2002), pp. 31-

current evoked by dopamine in rat subthalamic neurones in vitro.

Insight into the organization of the motor and non-motor symptoms in Parkinson's disease (PD) is critical for understanding the role of basal ganglia in the control of behavioral expression. Motor symptoms are generally characterized by hypokinesia-bradykinesia, resting tremor, muscular rigidity and posture-gait disabilities (Morris et al., 1994; Murrey et al., 1978). Sleep disturbances are major non-motor symptoms, which include insomnia, narcolepsy-like sleep attack and rapid eye movement (REM) sleep behavioral disorder (RBD) (Ferini-Strambi & Zucconi, 2000; Iranzo et al., 2006; Postuma et al., 2010; Schenck, 1996), in addition to disturbances of emotional expression and impairments of cognitive and executive functions (Aarsland et al., 2010).

It has been well established that the cortico-basal ganglia loops (C-BG loop) contribute to the volitional and intentional control of movements (Delong & Wichmann, 2007). Basal ganglia outflow directly toward to the midbrain of the brainstem (basal ganglia-brainstem system; BG-BS system) has been recently recognized with respect to the regulation of muscle tone and posture-gait synergy (Takakusaki et al., 2003a, 2004c). It has been suggested that the BG-BS may also contribute to the modulation of vigilance states (Takakusaki et al., 2004c, 2005). Fundamental structures involved in the control of posture and locomotion and those in the muscle tone regulation during awake-sleep states exist in the brainstem and spinal cord (Chase & Morales 1990; Takakusaki et al., 1993, 1994, 2004a, 2006). The importance of the midbrain area including the pedunculopontine tegmental nucleus (PPN) has been particularly recognized in relation to these functions (Palphill & Lozano 2000; Datta, 2002; Rye 1997). The PPN and a vicinity of this nucleus (PPN area) receive excitatory projections from the cortical motor areas (Matsumura et al., 2000) and the limbic system via the hypothalamus. The PPN is also a major target of GABAergic projections from the basal ganglia output nuclei (Moriizumi et al., 1988; Rye et al., 1987; Span & Grofova, 1991; Lavoie & Parent 1994).

The purpose of this review is to facilitate understanding the pathophysiological mechanism of motor and non-motor functions in PD. For this, we first refer general framework in the central nervous system for movement control in relation to volitional, emotional and

Possible Contribution of the Basal Ganglia

Brainstem System to the Pathogenesis of Parkinson's Disease 435

behaviors therefore may require following the three processes; "*volitional process"* (Fig.1A(1))*,* "*emotional process"* (Fig.1A(2)) and "*automatic processes"* (Fig.1A(3))*.* The volitional process is derived from intentionally-elicited motor commands arising from the cerebral cortex based on volitional and cognitive references. This process requires cortical information processing and is executed by the corticoreticular and corticospinal projections. The emotional process is elicited by emotional reference via projections from the limbichypothalamus to the brainstem. This contributes to the emotional motor behaviors including fight or flight reactions. Regardless of whether the locomotion is volitional or emotional, it is accompanied by the automatic processes that are evoked by sequential activation of basic motor programs in the brainstem and spinal cord. The cerebellum regulates volitional and automatic processes by acting on the cerebral cortex and the brainstem, respectively. Sensory feedback via spinocerebellar tract plays an important role in this operation. The basal ganglia control these processes via loops with the cerebral cortex, brainstem and the limbic system. Because output of the basal ganglia is altered in

basal ganglia disorders, all these movement processes can be disturbed.

**2.2 Mechanisms of integrating posture and locomotion by subcortical structures**  In animal experiments, decerebrate cat preparation has been used to examine subcortical mechanisms of controlling posture and locomotion. When the decerebration was made at the precollicular-postmammillary level (x in Fig.2A), a cat maintained reflex standing posture due to decerebrate rigidity (mesencephalic cat). Repetitive microelectrical stimulation (50 Hz, 30 μA) applied to the cuneiform nucleus (CNF; a blue point in Fig.2B) bilaterally increased the level of extensor (soleus) muscle tone, and then elicited stepping movements which were developed to locomotion by moving a treadmill (an arrowhead in Fig.2Ba). However the same type of stimuli applied to the ventral part of the PPN (red point in Fig.2B) induced muscular atonia, which lasted even after termination of the stimulation (Fig. 2Bc). Stimulation between these two sites (a green point in Fig.2C) evoked stepping movements followed by muscular atonia (Fig.2Bb). Stimulation of the locus coeruleus (LC, an orange point in Fig.2B) bilaterally increased extensor muscle tone (Fig.2Bd). Generally the locomotion evoking sites (blue circles in Fig.2D), i.e. the midbrain locomotor region (MLR), were located in the CNF, while the inhibitory region was located in the PPN (red circles in in Fig.2C). Neurons between these regions may be involved in both locomotion and muscular atonia. As show in Fig.2D, cholinergic neurons were abundantly distributed in the area corresponding to the inhibitory region, indicating that an activation of

cholinergic neurons requires muscle tone suppression (Takakusaki et al., 2003a).

Our current perception of neuronal mechanisms of controlling postural muscle tone and locomotion is shown in Fig.3A on the basis of previous studies (Grillner 1981; Mori 1987; Rossignol 1996; Takakusaki et al., 2004b, 2006). Three locomotor regions are identified. They are the MLR, the subthalamic locomotor region (SLR) and the cerebellar locomotor region (CLR). Signals from the MLR may activate "muscle tone excitatory system" and "locomotor system or rhythm generating system". The former is composed of monoaminergic descending pathways such as the coerulospinal and raphespinal tracts, and excitatory reticulospinal tract arising from the ventromedial medullary reticular formation (v-MRF) which approximately corresponds to the nucleus reticularis magnocellularis. The latter is composed of the excitatory reticulospinal tract and central pattern generators (CPG) in the spinal cord. Cortical projections to the MLR have not yet been identified. It is possibly

automatic aspects. In the second section we demonstrated recent findings obtained in animal experimentation how BG-BS system controlled postural muscle tone and locomotion. Then we propose hypothetical models that can provide rational explanations of motor disturbances in PD. In the third, final, section, we consider the role of the BG-BS systems in non-motor functions with special reference to the regulation of arousal state and awakesleep states.
