**5. Concluding thoughts**

448 Etiology and Pathophysiology of Parkinson's Disease

Behavioral arousal requires an activation of dopaminergic projections arising from the SNc to the striatum and the ventral tegmental area (VTA) to the prefrontal cortex and the limbic system. The nigrostriatal projection is responsible for basal ganglia related motor functions. The mesocortical projection contributes to volitional expression and attention, and the mesolimbic projection is involved in emotional expression. On the other hand, ARAS plays a major role in the electroencephalographic arousal. An activation of the two arousal systems is required to maintain arousal state that enables alert, attention and cognition (Jones 1991). Because PPN has dense cholinergic and non-cholinergic excitatory connections with dopamine (DA) neurons in the SNc and other basal ganglia nuclei (Futami et al., 1994; Kitai, 1998; Takakusaki et al., 1996), these projections appear to play a role in more specific subcortical integration of motor and non-motor functions such as behavioral arousal, attention and reward (Kitai, 1998). For example, an injection of muscimol into the PPN reduced the speed and amount of arm movements and delayed the onset of movements but the accuracy was rather maintained (Matsumura and Kojima, 2001). Moreover, Kojima et al. (1997) demonstrated that kainic acid-induced lesion in the unilateral PPN induced hemiparkisonism which was observed in the contralateral side of the injection. From these findings they suggest that the PPN may thus facilitate the voluntary limb movements

Midbrain DA neurons are also involved in the predictive reward which is specifically linked with reinforcement behaviors. DA neurons are activated by rewarding events that are better than predicted, remain uninfluenced by events that are worse than predicted (Hikosaka et al., 2000; Schultz, 1998). Kobayashi et al. (2002) demonstrated that PPN neurons showed multi-modal activities during saccade tasks in alert monkey; their activities were related to the arousal levels, execution and preparation of movements, the level of task performance, and reward. Therefore the PPN may serve as an integrative interface between the various signals required for performing purposive behaviors (Kobayashi et al., 2004). We postulate that the PPN facilitates, possibly via dopaminergic systems, the central processes for motor command generation and extrinsic sensory processing by modulating arousal and attentive

In non-human primate, limited lesions of the striatum induce deficits in rule acquisition (Divac 1972), cognition (Taylor et al., 1990), working memory performance (Goldman-Rakic, 1987) and selected attention (Battig et al., 1962). Laplane et al. (1984) reported a patient with restricted bilateral pallidal lesions who was appeared apathetic and unconcerned or attention deficits, and his affect was flattened and emotional responses were blunted in the absence of any motor disorder or pure psychic akinesia. These symptoms were also described in progressive supranuclear palsy (PSP) in which major lesions were observed in the subcortical areas including the PPN. Because loss of cholinergic PPN neurons were observed not only in PSP (75-80%) but also PD (43-57%) (Hirsch et al., 1987; Jellinger, 1988; Zweig et al., 1987, 1989), the loss of cholinergic PPN neurons in both diseases could attribute to attentive and cognitive impairments and sleep deficiencies in these diseases (Scarnati &

Both neuroanatomical (von Krosigk et al., 1992; Smith & Bolam, 1990) and electrophysiological (Häusser & Yung, 1994; Saitoh et al., 2004; Paladini et al., 1999) studies demonstrated that dopaminergic neurons, as well as cholinergic neurons, receive GABAergic inhibitory effects from the basal ganglia, particularly from the SNr. Consequently a BG-BS system appears to involve the interdigitation of motor information

**4.3 Disturbances of arousal state, attention and cognition** 

through its excitatory connections with the DA neurons.

states.

Florio, 1997).

The basal ganglia controls various function by acting on thalamocortical loop (C-BG loop) and the brainstem (BG-BS system). There are two key mechanisms for the operation by the basal ganglia circuit. One is sequential information processing, which would enhance the temporal contrast of the excitability of the target systems so that only the selected motor program could be appropriately executed, whereas other competing programs can be cancelled. The other is sustained output from the basal ganglia, which may control the degree of freedom of the excitability of the target systems during movements. We suggest that following roles can be played by the BG-BS system. First this system is involved in the automatic or unconscious control of movements that accompany voluntary movements. Second, the BG-BS systems may be involved in the maintenance of arousal and attentive states and in the regulation of REM sleep. Because output from the basal ganglia is thought to be overactive in PD, dysfunction of the BG-BS system in addition to that of C-BG loop can be seriously involved in motor and non-motor functions in this disease.
