Altered expression of parvalbumin and calbindin in interneurons within the primary visual cortex of neonatal enucleated hamsters

In the present study, we tested the hypothesis that the expression of calcium binding proteins (CaBPs), parvalbumin (PV), calretinin (CR) and calbindin (CB), is dependent upon sensory experience as emphasized in visual deprivation and deafferentation studies. The expression of CaBPs was studied in interneurons within the primary and extrastriate visual cortices (V1, V2M, V2L) and auditory cortex (AC) of adult hamsters enucleated at birth. The effects of enucleation were mainly confined to area V1 where there was a significant volume reduction (26%) and changes in the laminar distribution of PV and CB immunoreactive (IR) cells. The density of PV-IR cell bodies was significantly increased in layer IV and reduced in layer V. Moreover, the density of CB-IR neurons was inferior in layer V of V1 in enucleated hamsters (EH) compared to controls. These results suggest that some features of the laminar distribution of specific CaBPs, in primary sensory cortices, are dependent upon or modulated by sensory input.     

Increased GABA levels in medial prefrontal cortex of young adults with narcolepsy

Study Objectives:

To explore absolute concentrations of brain metabolites including gamma amino-butyric acid (GABA) in the medial prefrontal cortex and basal ganglia of young adults with narcolepsy.

Design:

Proton magnetic resonance (MR) spectroscopy centered on the medial prefrontal cortex and the basal ganglia was acquired. The absolute concentrations of brain metabolites including GABA and glutamate were assessed and compared between narcoleptic patients and healthy comparison subjects.

Setting:

Sleep and Chronobiology Center at Seoul National University Hospital; A high strength 3.0 Tesla MR scanner in the Department of Radiology at Seoul National University Hospital.

Patients or Participants:

Seventeen young adults with a sole diagnosis of HLA DQB₁ 0602 positive narcolepsy with cataplexy (25.1 ± 4.6 years old) and 17 healthy comparison subjects (26.8 ± 4.8 years old).

Interventions:

N/A.

Measurements and Results:

Relative to comparison subjects, narcoleptic patients had higher GABA concentration in the medial prefrontal cortex (t = 4.10, P <0.001). Narcoleptic patients with nocturnal sleep disturbance had higher GABA concentration in the medial prefrontal cortex than those without nocturnal sleep disturbance (t = 2.45, P= 0.03), but had lower GABA concentration than comparison subjects (t = 2.30, P = 0.03).

Conclusions:

The current study reports that young adults with narcolepsy had a higher GABA concentration in the medial prefrontal cortex, which was more prominent in patients without nocturnal sleep disturbance. Our findings suggest that the medial prefrontal GABA level may be increased in narcolepsy, and the increased medial prefrontal GABA might be a compensatory mechanism to reduce nocturnal sleep disturbances in narcolepsy.

Citation:

Kim SJ; Lyoo IK; Lee YS; Sung YH; Kim HJ; Kim JH; Kim KH; Jeong DU. Increased GABA levels in medial prefrontal cortex of young adults with narcolepsy. SLEEP 2008;31(3):342-347.     

Development of brain stimulation reward in the medial prefrontal cortex: Facilitation by prior electrical stimulation of the sulcal prefrontal cortex

Electrical stimulation of the medial prefrontal cortex (MC) in rats delivered daily for seven days causes a marked improvement in the rate of acquisition of a self-stimulation response. In the present experiment, we looked at whether we could get the same facilitatory effect on self-stimulation of the MC by delivering pre-training stimulation to other points in the brain anatomically related to the MC. Electrical stimulation of the lateral hypothalamus was without effect. However, electrical stimulation of the sulcal prefrontal cortex (SC) either contralateral or ipsilateral to the MC electrode did facilitate acquisition of self-stimulation of the MC. Thus the SC and MC would appear to be part of the same substrate controlling the development of positive reinforcement in the MC.     

Catalepsy after microinjection of haloperidol into the rat medial prefrontal cortex

Summary To investigate the behavioural role of mesocortical dopamine innervation we performed bilateral microinjections of haloperidol into various parts of the rat frontal cortex and into adjacent subcortical forebrain structures. Haloperidol (2.5 g/ 0.5 l) locally injected into the medial prefrontal cortex or into the rostral part of the neostriatum resulted in the development of catalepsy as measured in the bar test. In contrast, injections of haloperidol into the nucleus accumbens, more caudal parts of the neostriatum, anterior cingulate cortex, rostral and lateral parts of the prefrontal cortex and into the lateral ventricles failed to induce catalepsy. It is concluded that blockade of dopamine receptors located in the rostral neostriatum and in the medial prefrontal cortex contributes to the development of haloperidol induced catalepsy.     

D2 and D4 dopamine receptor mRNA distribution in pyramidal neurons and GABAergic subpopulations in monkey prefrontal cortex: implications for schizophrenia treatment

D2 and D4 dopamine receptors play an important role in cognitive functions in the prefrontal cortex and they are involved in the pathophysiology of neuropsychiatric disorders such as schizophrenia. The eventual effect of dopamine upon pyramidal neurons in the prefrontal cortex depends on which receptors are expressed in the different neuronal populations. Parvalbumin and calbindin mark two subpopulations of cortical GABAergic interneurons that differently innervate pyramidal cells. Recent hypotheses about schizophrenia hold that the root of the illness is a dysfunction of parvalbumin chandelier cells that produces disinhibition of pyramidal cells. In the present work we report double in situ hybridization histochemistry experiments to determine the prevalence of D2 receptor mRNA and D4 receptor mRNA in glutamatergic neurons, GABAergic interneurons and both parvalbumin and calbindin GABAergic subpopulations in monkey prefrontal cortex layer V. We found that around 54% of glutamatergic neurons express D2 mRNA and 75% express D4 mRNA, while GAD-positive interneurons express around 34% and 47% respectively. Parvalbumin cells mainly expressed D4 mRNA (65%) and less D2 mRNA (15–20%). Finally, calbindin cells expressed both receptors in similar proportions (37%). We hypothesized that D4 receptor could be a complementary target in designing new antipsychotics, mainly because of its predominance in parvalbumin interneurons.     

Further characterization of sleep-active neuronal nitric oxide synthase neurons in the mouse brain

We recently demonstrated that Fos is induced in a subpopulation of cortical neuronal nitric oxide synthase (nNOS)-immunoreactive neurons in three rodent species both during spontaneous sleep (SS) and recovery sleep (RS) after a period of sleep deprivation (SD); the proportion of cortical Fos⁺/nNOS neurons was significantly correlated with non-REM (NREM) sleep delta energy. The present study was undertaken to evaluate the specificity of this state-dependent activation of cortical nNOS cells. The percentage of nNOS neurons that expressed Fos during SD and RS was determined in nine subcortical brain regions and the cortex of the mouse brain; a significantly greater proportion of Fos⁺/nNOS neurons was observed during RS only in the cortex and in none of the nine subcortical regions. The proportion of calretinin-, calbindin- and parvalbumin-immunoreactive cortical interneurons that expressed Fos during SD and RS was also determined. In contrast to cortical nNOS neurons, a higher percentage of Fos⁺/calbindin neurons was found during SD than RS; there were no differences in the proportions of Fos-expressing parvalbumin or calretinin neurons between these conditions. Since the nNOS and calretinin cortical interneuron populations overlap extensively in the mouse brain, triple-labeling with these two phenotypic markers and Fos was undertaken in mice from the RS group to determine which combination of markers could best identify the rare “sleep-active” cortical interneuron population. The proportions of both Fos⁺/nNOS neurons and Fos⁺/nNOS/calretinin neurons far exceeded the proportion of Fos⁺/calretinin neurons during RS, but the proportions of these two cell types were not significantly different during RS. Thus, functional activation of nNOS neurons during sleep appears to be restricted to the cerebral cortex and cortical nNOS cells and nNOS/calretinin cells collectively define a cortical interneuron population that is activated during sleep.     

Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat

The medial prefrontal cortex (mPFC) participates in several higher order functions including selective attention, visceromotor control, decision making and goal-directed behaviors. We discuss the role of the infralimbic cortex (IL) in visceromotor control and the prelimbic cortex (PL) in cognition and their interactions in goal-directed behaviors in the rat. The PL strongly interconnects with a relatively small group of structures that, like PL, subserve cognition, and together have been designated the 'PL circuit.' These structures primarily include the hippocampus, insular cortex, nucleus accumbens, basolateral nucleus of the amygdala, the mediodorsal and reuniens nuclei of the thalamus and the ventral tegmental area of the midbrain. Lesions of each of these structures, like those of PL, produce deficits in delayed response tasks and memory. The PL (and ventral anterior cingulate cortex) (AC) of rats is ideally positioned to integrate current and past information, including its affective qualities, and act on it through its projections to the ventral striatum/ventral pallidum. We further discuss the role of nucleus reuniens of thalamus as a major interface between the mPFC and the hippocampus, and as a prominent source of afferent limbic information to the mPFC and hippocampus. We suggest that the IL of rats is functionally homologous to the orbitomedial cortex of primates and the prelimbic (and ventral AC) cortex to the lateral/dorsolateral cortex of primates, and that the IL/PL complex of rats exerts significant control over emotional and cognitive aspects of goal-directed behavior.     

Oseltamivir (Tamiflu) increases dopamine levels in the rat medial prefrontal cortex

Oseltamivir (Tamiflu), a neuraminidase inhibitor, is effective for treating both seasonal flu and H5N1 influenza A virus infection. Oseltamivir is generally well tolerated, and its most common adverse effects are nausea and vomiting. However, neuropsychiatric behaviors including jumping and falling from balconies by young patients being treated by oseltamivir have been reported from Japan; this has led to warnings against its prescribing by many authorities. The pharmacological mechanism of the neuropsychiatric effects of oseltamivir remains unclear. Many studies reported that changes in neurotransmission and abnormal behaviors are closely related. We investigated the changes in dopamine and serotonin metabolism after systemic administration of oseltamivir in the medial prefrontal cortex (mPFC) of rats by using microdialysis. After systemic administration of oseltamivir (25mg/kg or 100mg/kg; intraperitoneally (i.p.)), extracellular dopamine in the mPFC was significantly increased as compared to the control values; 3,4-dihydroxyphenylacetic acid and homovanillic acid, the metabolites of dopamine, had also increased significantly. Serotonin was unchanged after the administration of oseltamivir. These findings suggest that oseltamivir increased dopamine release in the mPFC; further, they suggest that the increase in dopamine during oseltamivir treatment may have caused abnormal behaviors in young patients. In cases where oseltamivir is prescribed to children, close observation is required.     

Different role of the ventral medial prefrontal cortex on modulation of innate and associative learned fear

Reversible inactivation of the ventral portion of medial prefrontal cortex (vMPFC) of the rat brain has been shown to induce anxiolytic-like effects in animal models based on associative learning. The role of this brain region in situations involving innate fear, however, is still poorly understood, with several contradictory results in the literature. The objective of the present work was to verify in male Wistar rats the effects of vMPFC administration of cobalt chloride (CoCl(2)), a selective inhibitor of synaptic activity, in rats submitted to two models based on innate fear, the elevated plus-maze (EPM) and light-dark box (LDB), comparing the results with those obtained in two models involving associative learning, the contextual fear conditioning (CFC) and Vogel conflict (VCT) tests. The results showed that, whereas CoCl(2) induced anxiolytic-like effects in the CFC and VCT tests, it enhanced anxiety in rats submitted to the EPM and LDB. Together these results indicate that the vMPFC plays an important but complex role in the modulation of defensive-related behaviors, which seems to depend on the nature of the anxiety/fear inducing stimuli.     

Early stress exposure impairs synaptic potentiation in the rat medial prefrontal cortex underlying contextual fear extinction

Traumatic events during early life may affect the neural systems associated with memory function, including extinction, and lead to altered sensitivity to stress later in life. We recently reported that changes in prefrontal synaptic efficacy in response to extinction trials did not occur in adult rats exposed to early postnatal stress (i.e. footshock [FS] stress during postnatal day 21–25 [3W-FS group]). However, identifying neurocircuitry and neural mechanisms responsible for extinction retrieval after extinction training have not been precisely determined. The present study explored whether synaptic transmission in the hippocampal-medial prefrontal cortex (mPFC) neural pathway is altered by extinction retrieval on the day after extinction trials using electrophysiological approaches combined with behavioral analysis. We also elucidated the effects of early postnatal stress on the synaptic response in this neural circuit underlying extinction retrieval. Evoked potential in the mPFC was enhanced following extinction retrieval, accompanied by reduced freezing behavior. This synaptic facilitation (i.e. a long-term potentiation [LTP]-like response) did not occur; rather synaptic inhibition was observed in the 3W-FS group, accompanied by sustained freezing. The behavioral deficit and synaptic inhibition observed in the 3W-FS group were time-dependently ameliorated by the partial N-methyl-d-aspartate (NMDA) receptor agonist d-cycloserine (15 mg/kg, i.p.). These findings suggest that the LTP-like response in the hippocampal-mPFC pathway is associated with extinction retrieval of context-dependent fear memory. Early postnatal stress appears to induce neurodevelopmental dysfunction of this neural circuit and lead to impaired fear extinction later in life. The present data indicate that psychotherapy accompanied by pharmacological interventions that accelerate and strengthen extinction, such as d-cycloserine treatment, may have therapeutic potential for the treatment of anxiety disorders, including posttraumatic stress disorder.     

Whole-brain mapping of monosynaptic afferent inputs to the CRH neurons in the medial prefrontal cortex of mice

Corticotropin-releasing hormone (CRH) neurons are densely distributed in the medial prefrontal cortex (mPFC), which plays a crucial role in integrating and processing emotional and cognitive inputs from other brain regions. Therefore, it is important to know the neural afferent patterns of mPFC^CRH neurons, which are still unclear. Here, we utilized a rabies virus-based monosynaptic retrograde tracing system to map the presynaptic afferents of the mPFC^CRH neurons throughout the entire brain. The results show that the mPFC^CRH neurons receive inputs from three main groups of brain regions: (1) the cortex, primarily the orbital cortex, somatomotor areas, and anterior cingulate cortex; (2) the thalamus, primarily the anteromedial nucleus, mediodorsal thalamic nucleus, and central medial thalamic nucleus; and (3) other brain regions, primarily the basolateral amygdala, hippocampus, and dorsal raphe nucleus. Taken together, our results are valuable for further investigations into the roles of the mPFC^CRH neurons in normal and neurological disease states. These investigations can shed light on various aspects such as cognitive processing, emotional modulation, motivation, sociability, and pain.     

Involvement of medial prefrontal cortex neurons in behavioral and cardiovascular responses to contextual fear conditioning

To explore the ventral medial prefrontal cortex (vMPFC) involvement in behavioral and autonomic fear-conditioned responses to context, vMPFC synaptic transmission was temporarily inhibited by bilateral microinjections of 200 nL of the nonselective synapse blocker CoCl(2) (1 mM). Behavioral activity (freezing, motor activity and rearing) as well as evoked cardiovascular responses (arterial pressure and heart rate) was analyzed. Rats were pre-exposed to the footshock chamber (context) and shock stimulus was used unconditioned stimulus. During re-exposure to context, conditioned rats spent 80% of the session in freezing while non-conditioned rats (no shock group) spent less than 15% of the session time in freezing. Conditioned rats had significantly lower activity scores than non-conditioned animals. Exposure to context increased mean arterial pressure (MAP) and heart rate (HR) of both groups. MAP and HR of the conditioned animals were markedly increased and remained at a high and stable level, whereas MAP and HR increases in non-conditioned animals were less pronounced and declined during the session. CoCl(2) microinjected in the vMPFC significantly reduced freezing and attenuated MAP and HR increase of the conditioned group. Cobalt-induced vMPFC inhibition also significantly reduced MAP and HR increase observed in non-conditioned animals, without any behavioral changes. The effect of vMPFC acute ablation on MAP and HR did not seem to be specific to the fear response because they were also evident in non-conditioned animals. The results indicate that vMPFC integrity is crucial for expression of fear-conditioned responses to context, such as freezing and cardiovascular changes, suggesting that fear-conditioned responses to context involve cortical processing prior to amygdalar output. They also indicate a cardiovascular response observed during re-exposure of non-conditioned rats to the context is completely dependent on vMPFC integrity.     

Retrospective and prospective coding of information: role of the medial prefrontal cortex

Summary Animals with sham-operations or medial prefrontal cortex lesions were trained in a task which required memory for short or long lists of items (spatial locations). On any one trial a rat is presented with 2, 4, 6, 8 or 10 items (spatial locations) on a 12-arm radial maze followed 15 min later by a win-shift test comprising a choice between a place previously visited and a novel place. Sham-operated animals showed an increase in errors as a function of set size (2 to 8 items) followed by a decrease in errors with a set size of 10 items suggesting the use of both retrospective and prospective memory codes. In contrast, animals with medial prefrontal cortex lesions made most of their errors for the longest list length reflecting an inability to shift from a retrospective to prospective memory code. The results are interpreted as support for a medial prefrontal cortex role in mediating a prospective code perhaps via knowlege systems based on temporal information.     

Selective neonatal depletion of dopamine has no effect on medial prefrontal cortex self-stimulation in the rat

The role of the dopaminergic input to the medial prefrontal cortex (MFC) on self-stimulation (SS) was investigated in adult rats injected neonatally with 6-hydroxydopamine (6-OHDA). Each subject on day 3 or 5 received bilateral intraventricular injection of 6-OHDA (total dose 200 micrograms, 50 micrograms/injection/2.5 microliters vehicle which contained 1 mg/ml ascorbic acid) or of the vehicle alone after pretreatment with desmethylimipramine (50 mg/kg i.p.) 30 min earlier. At 150 days of age, the animals were implanted with monopolar (100 microns) stainless steel electrodes in the MFC. One long (10 h) and 5 short (2 h) SS sessions resulted in similar percentages of responders for the brain reward in test and control subjects, and similar response rates in both groups. Biochemical assays of the levels of norepinephrine (NE) and dopamine (DA) in the frontal cortex showed depletion of DA 90% in the test animals, but no depletion of NE. Histochemical fluorescence visualization of the catecholamine input verified the biochemical results in the MFC. These results are viewed as negative evidence for the hypothesis that DA innervations in the MFC are critical neural substrates for SS, and suggest that activation of intrinsic neurons in the MFC are responsible for SS in the region.     

Cholinergic neurons in the rat cerebral cortex demonstrated by immunohistochemical localization of choline acetyltransferase

The presence of cholinergic neurons in rat cerebral cortex was demonstrated by immunohistochemical localization of choline acetyltransferase, the enzyme synthesizing the neurotransmitter acetylcholine. The stained neurons were found throughout the entire cortex and were present in layers II–VI. Two morphologically d distinct classes of cholinergic neurons have been identified and compared with those neurons containing acetylcholinesterase.     

Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence

A growing body of work has documented sex differences in many behavioral, neurochemical, and morphological responses to stress. Chronic stress alters morphology of dendrites in medial prefrontal cortex in male rats. However, potential sex differences in stress-induced morphological changes in medial prefrontal cortex have not been examined. Thus, in Experiment 1 we assessed dendritic morphology in medial prefrontal cortex in male and female rats after chronic stress. Male and female rats underwent either 3 hours of restraint daily for 1 week or were left unhandled except for weighing. On the final day of restraint, all rats were euthanized and brains were stained using a Golgi–Cox procedure. Pyramidal neurons in layer II–III of medial prefrontal cortex were drawn in three dimensions, and morphology of apical and basilar arbors was quantified. In males, stress decreased apical dendritic branch number and length, whereas in females, stress increased apical dendritic length. In Experiment 2, we assessed whether estradiol mediates this stress-induced dendritic hypertrophy in females by assessing the effects of restraint stress on female rats that had received either ovariectomy with or without 17-β-estradiol replacement or sham ovariectomy. Brains were processed and neurons reconstructed as described in Experiment 1. Both sham-operated and ovariectomized rats with estradiol implants showed stress-induced increases in apical dendritic material, whereas ovariectomy without estradiol replacement prevented the stress-induced increase. Thus, the stress-induced increase in apical dendritic material in females is estradiol-dependent.     

Orexin-A excites pyramidal neurons in layer 2/3 of the rat prefrontal cortex

The arousal peptides, orexins, play an important role in regulating the function of the prefrontal cortex (PFC). Although orexins have been shown to increase the excitability of deep-layer neurons in the medial prefrontal cortex (mPFC), little is known about their effect on layer 2/3, the main intracortical processing layer. In this study, we investigated the effect of orexin-A on pyramidal neurons in layer 2/3 of the mPFC using whole-cell recordings in rat brain slices. We observed that orexin-A reversibly depolarized layer 2/3 pyramidal neurons through a postsynaptic action. This depolarization was concentration-dependent and mediated via orexin receptor 1. In voltage-clamp recordings, the orexin-A-induced current was reduced by the replacement of internal K(+) with Cs(+), removal of external Na(+), or an application of flufenamic acid (an inhibitor of nonselective cation channels). A blocker of Na(+)/Ca(2+) exchangers (SN-6) did not influence the excitatory effect of orexin-A. Moreover, the current induced by orexin-A reversed near E(k) when the external solution contained low levels of Na(+). When recording with Cs(+)-containing pipettes in normal external solution, the reversal potential of the current was approximately -25 mV. These data suggest an involvement of both K(+) channels and nonselective cation channels in the effect of orexin-A. The direct excitatory action of orexin-A on layer 2/3 mPFC neurons may contribute to the modulation of PFC activity, and play a role in cognitive arousal.     

Role of the prelimbic cortex in the acquisition, re-acquisition or persistence of responding for a drug-paired conditioned reinforcer

The medial prefrontal cortex has been suggested to play a role in drug addiction due to its involvement in the reinstatement of drug seeking. In the present study, the role of the prelimbic cortex in persistent responding maintained by the earned presentations of a drug-paired conditioned reinforcer was studied. Temporary inactivation of the prelimbic, prefrontal cortex of rats had no effect on this persistent response, but did impair its initial acquisition, maintained by the drug-paired conditioned reinforcer. The lesion also impaired re-acquisition of this response after extinction by omission of the contingent conditioned reinforcer. These results suggest that the prelimbic cortex has a selective role in the acquisition, or re-acquisition, of instrumental responses for drug-paired conditioned reinforcers, that may be important in relapse to drug seeking. Anatomical controls with placements in the infralimbic cortex showed longer-lasting impairments in the acquisition of this response, consistent with the suggestion that the prelimbic and infralimbic cortices mediate different aspects of behavior, with the infralimbic being more specialized for habits. The implications of the present findings toward the understanding of drug seeking and relapse behaviors and the separate brain systems that may underlie them are discussed.     

The firing activity of pyramidal neurons in medial prefrontal cortex and their response to 5-hydroxytryptamine-1A receptor stimulation in a rat model of Parkinson's disease

The changes in the firing rate and firing pattern of pyramidal neurons in medial prefrontal cortex (mPFC) and the effects of selective 5-hydroxytryptamine-_1A (5-HT_1A) receptor agonist (R)-(+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) and antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridylcyclohexane carboxamide maleate salt (WAY-100635) on the firing activity of the neurons were studied in sham-lesioned rats and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The lesion of the SNc increased the firing rate of pyramidal neurons significantly compared to sham-lesioned rats, and the firing pattern of these neurons also changed significantly towards a more burst-firing. The systemic administration of 8-OH-DPAT at doses in the range of 0.5–128 μg/kg showed an excitatory-inhibitory effect on the firing rate of pyramidal neurons in mPFC of sham-lesioned rats. At lower doses, 0.5–32 μg/kg, it evoked excitation of the neurons, and at a high dose, i.e. 128 μg/kg, inhibited the activity of the neurons. In contrast to sham-lesioned rats, 8-OH-DPAT, at the same doses, showed no excitatory effect in the lesioned rats although the inhibitory phase of the effect of 8-OH-DPAT on the firing rate of pyramidal neurons in mPFC was still present. Furthermore, the local application of 8-OH-DPAT, 5 μg, in mPFC inhibited the firing rate of pyramidal neurons in sham-lesioned rats, while having no effect on firing rate in the lesioned rats. The excitatory or inhibitory effects of 8-OH-DPAT were reversed by WAY-100635, indicating that these effects are mediated by 5-HT_1A receptor. Altogether, these results indicate that the lesion of the SNc leads to hyperactivity of pyramidal neurons in mPFC and the abnormality of response of these neurons to 5-HT_1A receptor stimulation, suggesting that mPFC may be involved in the pathophysiology of the psychiatric disturbance of Parkinson's disease.