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Bone marrow stromal cells (BMSCs) are an interesting subject of research because they have characteristics of mesenchymal stem cells. We investigated intracellular Ca(2+) signaling in rat BMSCs. Agonists for purinergic receptors increased intracellular Ca(2+) levels ([Ca(2+)](i)). The order of potency followed ATP = UTP > ADP = UDP. ATP-induced rise in [Ca(2+)](i) was suppressed by U73122 and suramin, but not by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), suggesting the functional expression of G protein-coupled P2Y(2) receptors. RT-PCR and immunohistochemical studies also showed the expression of P2Y(2) receptors. [Ca(2+)](i) response to UTP changed with cell density. The UTP-induced rise in [Ca(2+)](i) was greatest at high density. V(max) (maximum Ca(2+) response) and EC(50) (agonist concentration that evokes 50% of V(max)) suggest that the amount and property of P2Y(2) receptors were changed by cell density. Note that UTP induced Ca(2+) oscillation at only medium cell density. Pharmacological studies indicated that UTP-induced Ca(2+) oscillation required Ca(2+) influx by store-operated Ca(2+) entry. Carbenoxolone, a gap junction blocker, enhanced Ca(2+) oscillation. Immunohistochemical and quantitative real-time PCR studies revealed that proliferating cell nuclear antigen (PCNA)-positive cells declined but the mRNA expression level of the P2Y(2) receptor increased as cell density increased. Co-application of fetal calf serum with UTP induced Ca(2+) oscillation at high cell density. These results suggest that the different patterns observed for [Ca(2+)](i) mobilization with respect to cell density may be associated with cell cycle progression.

ヒトの認知機能の発現と制御に関する中枢神経機序を明らかにするため、サルに多くの随意運動課題を訓練し、種々の大脳皮質に埋め込んだ対電極（表面電極と深部電極から構成）を用いて大脳皮質フィールド電位を測定し、種々の認知機能と関連づけて検討した。得られた研究成果の中、本論文では主に前頭葉と頭頂葉がどんな認知機能の発現と制御に関与するかにつき述べた。さらに種々の認知機能への小脳の関与、及び小脳切除により低下した運動野の運動機能の頭頂葉による代償機能について述べ、リハビリなど臨床応用にも言及した。さらに、高次脳機能への長期間運動の影響を研究するため、「さる運動装置」を民間企業と共同開発した。本装置で2匹のサルに下肢運動を長期間行わせた後、外部刺激始動性上肢運動の学習中に大脳皮質フィールド電位の計測と行動学的観察を行って対照群と比較検討し、学習能力向上への長期間運動の有用性を明らかにした。

We examined electrophysiological and molecular changes of the thalamocortical system after thalamic degeneration in Purkinje cell degeneration (pcd) mice. In pcd mice, neurons in specific thalamic nuclei including the ventral medial geniculate nucleus began to degenerate around postnatal day 50, whereas the visual thalamic nucleus and nonspecific thalamic nuclei remained almost intact. In association with the morphological changes, auditory evoked potentials in the primary auditory cortex (AC) began to decrease gradually. Fast Fourier transform analysis of spontaneous cortical field potentials revealed that fast oscillation (FO) around 25 Hz occurred in the AC but not in the visual cortex. Quantitative mRNA analysis demonstrated that expression of the N-methyl-D-aspartate (NMDA) receptor was up-regulated in the AC but not in the visual cortex. Systemic administration of an NMDA antagonist abolished the FO in the AC. These results indicate that increased NMDA activity may cause the FO in the AC of pcd mice.

本研究の目的は、サルの頚部水平回転運動前に生じる大脳皮質活動を明らかにすることである。玄番らはサルに上肢運動(或いは発声)を行わせた際、各大脳皮質の表面で陰性、表面から2-3mm深部で陽性の準備電位(運動に約1秒先行して出現する電位)が発生することを既に報告している。そこで、サルが自発的に首を水平回転できるように訓練し、回転運動時の大脳皮質フィールド電位は対電極(表面電極、深部電極)で記録し、運動の軌跡(メカノグラム)はロータリーエンコーダーというトランスジューサーを介して記録、解析した。電位は、左右大脳皮質の運動前野、運動野、体性感覚野、頭頂連合野に麻酔下で埋め込まれた多数の電極から同時記録し、運動開始時点で通常100回加算平均した。なお記録後、データを速度別に分ける場合には、サルに300回以上続けて回転運動を行わせた。その結果、運動前野、運動野、体性感覚野、それと頭頂連合野の頭頂間溝の前壁・後壁何れにも準備電位が出現した。そして、運動前野、運動野や体性感覚野の電位には速度変化による一定の変化があるようには見えないが、一方、前壁・後壁においては速度が増すごとに、準備電位の運動開始時振幅、運動開始前面積の両方とも大きくなっていることがわかった。以上から、後部頭頂皮質は頚部水平回転運動の予測性速度制御に関与することが判明した。, A purpose of this study is to clarify brain cortex activity to occur before simian cervical horizontal rotary motion. When we let a monkey perform superior limb movement (or we utter), Gemba has already reported what readiness potential (potential we go ahead of exercise for about 1 second, and to develop) which is positive in two or three mm deep part produces from negative, the surface at each cerebrocortical surface. Therefore a monkey trained a neck spontaneously to be able to turn horizontally and recorded brain cortex field potential at the time of rotary motion with counter electrode (surface electrode, depth electrode) and a kinetic trace (mechanogram) went through a rotary encoder and the transducer which said and analyzed a record. We recorded potential from a lot of electrodes buried in premotor area of right and left brain cortex, motor area, somatic sensory area, parietal association area under anesthesia at the same time and usually averaged 100 times of addition by exercise base line. In addition, after a record, we let a monkey perform rotary motion more than 300 times successively when we distributed data according to speed. As a result, readiness potential developed to premotor area, motor area, somatic sensory area, it and both paries anterior / paries posteriors of intraparietal sulcus of parietal association area. And there did not seem to be a constant change by a speed change, but potential of premotor area, motor area and somatic sensory area understood amplitude, that we grew big with both exercise preinitiation areas at exercise start time of readiness potential whenever speed increased in one, a paries anterior / a paries posterior. Thus, it became clear that rear vertex cortex contributed to predictability speed control of cervical horizontal rotary motion.

Cortical field potentials were recorded by electrodes implanted chronically on the surface and at a 2.0-3.0 mm depth in various cortices in monkeys performing self-paced finger, toe, mouth, hand or trunk movements. Surface-negative, depth-positive potentials (readiness potential) appeared in the posterior parietal cortex about 1.0 s before onset of every self-paced movement, as well as in the premotor, motor and somatosensory cortices. Somatotopical distribution was seen in the readiness potential in the posterior parietal cortex, although it was not so distinct as that in the motor or somatosensory cortex. This suggests that the posterior parietal cortex is involved in preparation for self-paced movement of any body part. This study contributes to the investigation of central nervous mechanisms of voluntary movements initiated by internal stimulus.

Thalamo-cortical projections to the posterior parietal cortex (PPC) were investigated electrophysiologically in the monkey. Cortical field potentials evoked by the thalamic stimulation were recorded with electrodes chronically implanted on the cortical surface and at a 2.0-3.0 mm cortical depth in the PPC. The stimulation of the nucleus lateralis posterior (LP), nucleus ventralis posterior lateralis pars caudalis (VPLc), and nucleus pulvinaris lateralis (Pul.l) and medialis (Pul.m) induced surface-negative, depth-positive potentials in the PPC. The LP and VPLc projected mainly to the superior parietal lobule (SPL) and the anterior bank of the intraparietal sulcus (IPS), and the Pul.m mainly to the inferior parietal lobule (IPL) and the posterior bank of the IPS. The Pul.l had projections to all of the SPL, the IPL and both the banks. The significance of the projections is discussed in connection with motor functions.

Auditory evoked potentials (AEPs) were recorded in the motor cortices (MC) with chronically implanted electrodes in the rat. Some of the AEPs in the MC, namely negative potentials on the surface and positive ones at a depth of 2 mm at latencies of about 50-150 ms, were abolished by limited bilateral lesions of the anterior perirhinal cortex (PERa) which was responsive to auditory stimulus, indicating that the AEPs in the MC were at least partially relayed in the PERa. The auditory response in the MC was prominently enhanced when water was supplied or the medial forebrain bundle was stimulated after auditory stimulus. These results indicate that the MC receives the reward associated auditory information from the PERa.

Stimulation of the anterior perirhinal cortex (PERa) induced marked surface-negative and depth-positive field potentials in the rat frontal motor cortex (MC) including the rostral and caudal forelimb areas. Injection of biotinylated dextran into the PERa densely labeled axon terminals in the superficial layers of the MC, where vigorous unit responses were evoked after PERa stimulation, indicated that the perirhinal-frontal projection preferentially activates the superficial layer neurons of the MC.

Thioacetamide (TAA), a hepatotoxin used to ascertain the role of astrocytes in hepatic encephalopathy, was administered to prepare four experimental groups of rats. (The TAA1D, TAA1.5D, TAA2D, and TAA2.5D group rats were perfusion fixated with formalin at 1, 1.5, 2, and 2.5 days, respectively, after initial administration of TAA. In addition, TAA was readministered to the TAA2D and TAA2.5D rats 24 h after the first dose.) Abnormalities of higher brain function and equilibrium that progressed with time were apparent in the rats receiving TAA. On the other hand, innate reflexes (e.g. pupillary reflex) were similar to those in the normal control group. Astrocyte cell areas in the hippocampus, neocortex, hypothalamus, cerebellum, and basal ganglia (striatum) from the TAA rats were significantly larger than in corresponding sites from the normal rats (maximum in TAA1D and TAA1.5D groups). However, there were no differences with respect to the midbrain. Any morphological difference was not observed in neurons between the hepatic encephalopathy and normal rats. Administration of TAA caused hepatic tissue injury that progressed over time. Surprisingly, encephalopathy was apparent even when hepatic injury was mild. These findings suggest that abnormalities in astrocytes, which precede any abnormal change in neurons, play a role in the development of hepatic encephalopathy.

Field potentials were recorded on self-paced hand and mouth movements with implanted electrodes on the surface and at 2.0-3.0 mm depth in respective cortical areas in seven monkeys. Surface-negative (s-N), depth-positive (d-P) premovement slow potentials were recorded in the prefrontal cortex only when the movements were performed with an intense motivation for a reward. Such a motivation-dependent activity was mainly obtained in the rostral bank of the arcuate sulcus on both sides (except for the inferior limb of the arcuate sulcus in the left hemisphere). Three of the seven monkeys were also tasked with visuo-initiated hand movements. As motivation for reward decreased, s-N, d-P potentials at a latency of about 80 ms after stimulus onset became gradually smaller in the rostral bank of the arcuate sulcus in the right hemisphere. These facts suggest that motivation-dependent activity is represented in the dorsolateral part of the prefrontal cortex in monkeys, and that the cortical part is involved in motivational functions as well as in cognitive functions.

Our MEG studies on the human frontal association cortex are briefly reviewed. (1) The no-go potential was first found at go/no-go reaction-time hand movement task with discrimination between different colour light stimuli in the prefrontal cortex of monkeys. The potential was recorded in human subjects with EEG over the scalp, but its current dipoles could be localized only by use of MEG, in the dorsolateral part of the frontal association cortex in both cerebral hemispheres. The function for no-go decision and subsequent suppressor action was thus substantiated in the human frontal cortex. (2) Utterance of a short noun in Japanese was found to be initially preceded by an activity in the lower lateral part of the frontal lobe and then by that around the central sulcus. The area of the former, often in both hemispheres, appears to correspond to Broca's motor speech centre and that of the latter, always in both hemispheres, to correspond to the motor-somatosensory cortices. (3) Intensive and continuous concentration on mental calculation and some `abstract' thinking for a few minutes were often associated with magnetic theta (5–7 Hz) wave bursts in the frontal part of the scalp. Dipole fitting suggested that the electrical current dipoles occur successively and scattered in wide areas of the frontal lobe on both sides. They are to be called “frontal mental theta wave”, revealing dynamic and active participation of the frontal lobe in mental functions.

By using enkephalin immunohistochemistry combined with retrograde fluorescent labelling, a great majority of neurons in the rat cerebellum sending their axons to the spinal cord were shown to contain enkephalin immunoreactivity. These neurons were numerous and clustered in the fastigial nucleus but far less abundant in other cerebellar nuclei. Enkephalin-immunoreactive fibers present in the ventral horn and the central cervical nucleus of upper cervical cord segments almost completely disappeared contralaterally following kainic acid-induced cell loss in the fastigial nucleus. The results indicate that fastigial and some other cerebellar nucleus neurons provide enkephalin-containing projections toward these spinal sites.

Activities of the frontal cortices in both cerebral hemispheres preceding utterance of a short word were recorded and analyzed with multichannel SQUID gradiometers. Light stimuli of two different colours of 500 ms duration were delivered in front of a subject at random time intervals and in irregular order of the different colours. The subject should respond to either of the stimuli by uttering a short word, e.g., ‘en’ (‘round’ in Japanese) or another by a short simple voice without meaning as a word, e.g., ‘e’ [e]. The initial sounds of both voices are to be the same, i.e., ‘e’ [e] in these examples. The 37 gradiometers covering either the left or the right frontal-parietal part of the hemisphere recorded different magnetic fields between the word and the simple voice. Magnetic fields averaged 100 times at the onset of the stimuli revealed that the utterance of a word is preceded by significant magentic field changes at a peak latency of 120–165 ms from the onset of light stimuli, whereas the utterance of a simple voice is not preceded by such changes. At a peak latency of 160–190 ms, about 20–40 ms before the start of perioral EMGs, both the utterances are commonly preceded by magnetic field changes. Dipole fittings based on these magnetic fields suggest that the earlier magnetic fields reflect electrical activities in the ventral lateral part of the frontal association area, usually in both left and right hemispheres, and that the later fields represent those in the sensorimotor area in both the hemispheres. That part of the frontal association area appears to be the centre for organizing words to speak and to correspond possibly to the Broca's speech area.

‘No-go potential’, specific to the no-go reaction in go/no-go reaction-time hand movement with discrimination between different colour light stimuli, was recorded with electrodes chronically implanted in the prefrontal cortex of monkeys. Similar potentials were widely distributed over frontal-parietal parts of the human scalp on the same no-go reaction. In this report, MEG measurement was made over the scalp of five healthy subjects in order to localize current sources responsible for the scalp potential. We found in- and outflow of magnetic fields over the dorsolateral frontal parts of the head, contra- and ipsilateral to the operant hand. These magnetic fields were most reasonably interpreted to be due to current dipoles localized in the dorsolateral parts of frontal lobes in both contra- and ipsilateral hemispheres, presumably in the prefrontal-premotor areas. No-go decision and subsequent suppression of voluntary movements are suggested to be one of the functional features of the human frontal association cortex, as in the case of monkeys.

Field potentials were recorded with electrodes implanted in various cortical areas while a monkey acquired a task of go/no-go reaction time hand movement with discrimination between tone stimuli of different frequencies. After a few weeks of training, a surface-negative, depth-positive (s-N, d-P) potential (no-go potential) emerged in the dorsal bank of the principal sulcus. As the potential increased in size in 1-3 months, the monkey gradually discriminated between go and no-go stimuli. The no-go potential is considered to be related to judgement not to move and suppression of motor execution. In the superior temporal gyrus, a s-N, d-P potential at a shorter latency than the no-go potential augmented in size on both go and no-go trials, as the monkey learned the discrimination task. The s-N, d-P potential in this gyrus may reflect an information processing prior to the discrimination in the prefrontal cortex.

Electrophysiological characterization of thalamo-cortical projections and cerebello-thalamo-cortical pathways was shown by acute experiments in which laminar field potential analysis of responses evoked in the cortex by stimulation of thalamic and cerebellar nuclei was performed in anesthetized monkeys. Based on the results, dynamic activities of cerebro-cerebellar interconnections on voluntary movements were recorded with electrodes chronically implanted in various cortical areas in unanesthetized monkeys and were correlated with their behaviours. Cortical field potentials change in learning processes of visually initiated reaction-time hand movement and in compensating processes after cerebellar hemispherectomy.

Cortical field potentials were recorded by surface and depth electrodes implanted in various cerebral cortices in monkeys on self-paced or visuo-initiated hand movements, or go/no-go discriminative hand movements with auditory or visual stimuli, and then analyzed. Readiness potentials appeared in the premotor, motor, somatosensory and posterior parietal cortices. The rostral bank of the left arcuate sulcus and the dorsal bank of the principal sulcus were found to be related to recognition learning and decision-making, respectively.

In the current studies, we characterized the molecular and cellular mechanism of cell death in Purkinje cell degeneration (pcd) mice using real-time quantitative PCR, immunohistochemistry, and Western blotting. It appears that endoplasmic reticulum (ER) stress is involved in this degeneration of Purkinje cells because ER stress-related substrates, such as CHOP and caspase 12, were strongly activated in Purkinje cells of pcd mice during the third postnatal (P) week. A significant increase in the expression of the ER-specific chaperone BiP suggested that unfolded protein responses were induced. We also found that Purkinje cells underwent apoptosis via the activation of caspase 3 and subsequent fragmentation of DNA. In addition to the activation of apoptosis in Purkinje cells, many activated microglial cells are found to be present in the molecular layer of the cerebellar cortex. In the later phase of degeneration, there was conspicuous expression of inducible nitric oxide synthase (iNOS), and some Purkinje cells were strongly labeled with an antibody to nitrotyrosine, suggesting that Purkinje cells in pcd mice are damaged by nitric oxide released from microglial cells. Administration of minocycline, which may inhibit iNOS expression, delayed the death of Purkinje cells in pcd mice and mildly improved their motor abilities. These findings suggest that ER stress participates in the degeneration of Purkinje cells and that activation of microglia accelerates Purkinje cell death in pcd mice.

Cortical field potentials were recorded by electrodes implanted chronically on the surface and at a 2.0 mm depth in various cortical areas in the left hemisphere in the rat during self-paced movements of the right forelimb. A surface-negative (s-N), depth-positive (d-P) cortical field potential appeared about 1.0 s (range: 0.5-1.5 s) before movement onset in the rostral (RFA) and caudal (CFA) forelimb areas of the motor cortex, and the somatosensory cortex, but not in the occipital cortex. Bipolar recording of electromyographic activities induced by the electrical stimulation of various cortical loci was also performed by pairs of steel electrodes inserted in the face, trunk, forelimb and hindlimb muscles on both sides. The stimulation of the forelimb motor cortex activated the face and/or forelimb muscles, while that of the somatosensory cortex generally activated several body part muscles including the forelimb muscle. Stronger stimulus intensity was requested to elicit the activities of most of the ipsilateral muscles to the cortex stimulated than the contralateral ones. The minimum intensity for inducing the forelimb muscle activity was lowest in the CFA among cortical areas producing the activity. The stimulation of cortical loci in which the s-N, d-P potential was recorded could induce muscle activities in the forelimb contralateral to the stimulation. It is suggested that the s-N, d-P potential is the readiness potential for activating muscles to initiate movement in the rat forelimb.

Seven rats were well trained to move lever to the left by right forelimb at self-pace (self-paced forelimb movements). Cortical field potentials associated with self-paced forelimb movements were recorded by electrodes implanted chronically on the surface and at a 2.0 mm depth in the forelimb motor cortex on the left side. A surface-negative, depth-positive potential starting about 1.0 s prior to the movement was recorded in the rostral part of the forelimb motor cortex. Further we found that the premovement potential was eliminated by the cerebellar hemispherectomy on the right side. This suggests the participation of the cerebellar hemisphere in preparing the activity of the motor cortex before self-paced forelimb movements in rats, by cerebello-thalamo-cortical projections.

The cerebello-thalamo-posterior parietal cortical projections were investigated electrophysiologically and morphologically in macaque monkeys. In anesthetized monkeys, electrical stimulation of every cerebellar nucleus evoked marked surface-positive, depth-negative (s-P, d-N) cortical field potentials in the superior parietal lobule and the cortical bank of the intraparietal sulcus, but no responses in the inferior parietal lobule. Tract-tracing experiments combining the anterograde method with the retrograde one indicated that the interposed and lateral cerebellar nuclei projected to the posterior parietal cortex mainly through the nucleus ventral lateralis caudalis of the thalamus. The significance of the projections is discussed in connection with cognitive functions.

Human motor speech function has been investigated neuropsychologically [1]. Recently by using non-invasive techniques measuring regional cerebral blood flows such as the functional magnetic resonance imaging (fMRI) [3] and the positron emission tomography (PET) [5], it was demonstrated that several cortical areas not only in the dominant hemisphere but also in the non-dominant hemisphere were activated during speech tasks. As these methods, however, have poor time resolution, it is difficult to get temporal information of the cortical activities. The magnetoencephalography (MEG) is suitable for investigating the temporal sequence of the activation of cortical areas on speech, since MEG has good temporal and spatial resolution. The present study is a trial to identify functionally the motor speech center in the frontal lobe of human cerebral cortex by using multichannel SQUID gradiometers. Parts of the results have been reported shortly [8].

Five monkeys vocalizing at self-pace (self-paced vocalization) were well trained to vocalize in response to a monkey call (audio-initiated vocalization). Field potentials associated with audio-initiated vocalizations were recorded by using electrodes which were implanted chronically on the surface and at a 2.0-3.0 mm depth in various cortical areas. A surface-negative (s-N), depth-positive (d-P) potential (at about 70 ms latency after stimulus onset) was recorded in the rostral bank of the inferior limb of the arcuate sulcus in the left hemisphere, in which an insignificant potential was associated with self-paced vocalizations. An s-N, d-P slow potential which occurred in the motor and somatosensory cortices with a latency of about 300 ms after stimulus, started about 700 ms before vocalizations. The duration and amplitude of this potential was substantially the same with those of the potential which occurred with self-paced vocalizations. Reaction times from stimulus onset to vocalization start were variable, but were about 0.9s on the average. The findings were discussed in connection with reaction-time hand movements.

Electrical stimulation of the caudoventral part of the anterior cingulate cortex (AC) evokes a species-specific vocalization in the guinea pig. After injections of glutamate receptor antagonists into the periaqueductal gray (PAG) regions where the AC projected, the forebrain-elicited vocalization (FEV) was suppressed completely. This result indicated that the FEV was induced at least partly by glutamatergic activation of PAG neurons. Injection of orphanin FQ/nociceptin (OFQ/N) into the PAG profoundly suppressed the FEV. This inhibitory effect of OFQ/N was not antagonized by naloxone, an opioid receptor antagonist. Since OFQ/N was reported to modify the glutamatergic transmission, the present results suggest that OFQ/N exerts influences upon the vocalization by regulating the glutamatergic inputs into the PAG.

The cerebellar projections to the ventral part of the frontal cortex were investigated in the Japanese monkey (Macaca fuscata). In anesthetized monkeys, stimulation of either the lateral or interposed cerebellar nucleus evoked marked surface-negative and depth-positive potentials in the face motor area (Mf) and the upper part of the ventral premotor area (PMv) on the contralateral side; responses were hardly recorded in the lower part of PMv including the areas related to the laryngeal movements. Stimulation of the medial cerebellar nucleus induced no significant responses in these areas. The results of the combined anterograde and retrograde tracing study indicated that the cerebellar nuclei projected to Mf and the upper part of PMv mainly through the nucleus ventralis posterior lateralis pars oralis and area X of the thalamus, respectively.

Fluid of the parotid gland was collected from seven human subjects during sleep and four subjects during wakefulness. It was continuously weighed during collection on an electronic balance. The weight value was processed on line by a personal computer, and circadian rhythm in connection with the flow rate of saliva was studied. One subject showed no secretion of saliva throughout sleep, but in the other subjects, saliva was secreted, although it was slight. There was no difference between the flow rate in rapid eye movement (REM) sleep and non-REM sleep. Every subject during wakefulness showed a flow rate in a range from a very high value to one almost equal to the value during sleep. The flow rate during wakefulness varied greatly, and there seemed to be no rhythmic pattern to it. With the aid of auditory or visual stimuli etc., the influence of emotional state upon parotid secretion was investigated in 12 subjects. It was found that the flow rate decreased significantly from an intense, passionate state to a relaxed, pleasant state, to a tense or uneasy state and was lowest in a passive, indifferent state, being almost the same as that during sleep. These findings suggest that secretion of parotid saliva depends more on emotional state than circadian rhythm.

Field potentials preceding vocalization were recorded with electrodes chronically implanted on the surface and at 2.0-3.0 mm depth in various cortical areas in three monkeys. Surface-negative, depth-positive (s-N, d-P) slow potentials prior to vocalization were recorded in the premotor (including the Broca's homology), motor and somatosensory cortices in both hemispheres, and the supplementary motor area in the cerebral hemisphere. Such premovement potentials were recorded also in the cingulate and prefrontal cortices when a monkey uttered with intense motivation for reward. Cerebellar hemispherectomy on the right side eliminated the s-N, d-P premovement potentials in the motor cortex and in the posterior bank of inferior limb of the arcuate sulcus (homolog of Broca's area) in the left hemisphere. Vocal tone contained less components in different frequencies, and its duration became more variable than before the operation. These facts suggest that the neocortical area homologous to the human speech area takes part in generation and control of monkey vocalization together with the cerebellum, possibly through cerebro-cerebellar interactions, against ideas so far offered on nonhuman primate vocalization.

Field potentials were recorded with electrodes implanted in various cortical areas while a naive monkey was learning reaction time hand movements with complex tone. When cortical surface-negative, depth-positive potential (at a latency of about 80 ms after a stimulus onset) appeared in the rostral bank of the inferior limb of the arcuate sulcus of the left cerebral hemisphere, and became gradually larger, the monkey began to respond to the stimulus with the movement. As the potential in the prefrontal (prearcuate) cortex and the cerebellar-mediated potential in the motor cortex gradually increased with further training, the movement became quicker and more skillful. Three naive monkeys achieved the movement with complex tone in shorter training days than the movement with pure tone; the movement with pure tone was not accompanied by any significant potential in the prefrontal cortex. It is deduced from the present study, and previous studies on visuo-initiated movements, that the prefrontal area, especially in the left hemisphere, plays a significant role for a monkey to associate a stimulus with appropriate motor execution.

The prefrontal cortex has been considered to be essential for initiative and reasoning behaviour in humans, and delayed and discriminative movement tasks in monkeys (see Fulton 1949; Rosenkilde 1979; Luria 1966; Fuster 1989). We have studied, in monkey experiments, the functional role of prefrontal cortex in the organization and control of conditioned hand movements in response to visual stimuli (see Sasaki 1985). Several parts of the prefrontal cortex, especially the prearcuate area, are very active in initiating simple reaction-time hand movements in response to visual stimuli and are important in processes of learning the movement (Sasaki and Gemba 1982). The wide areas of the prefrontal cortex together with the premotor cortex were found to be continuously excited between warning and imperative stimuli, and to produce contingent negative variation (CNV) (Sasaki et al. 1990; Gemba et al. 1990).

The functional role of the cerebellum in voluntary movement was investigated by local cooling of the cerebellar nuclei in three Japanese monkeys which performed hand movement tasks in response to visual stimuli. We implanted electrodes in various areas of the cerebral hemispheres to record field potentials in the cortex, and examined effects of the cooling upon the movement and field potentials. Cooling of the dentate nucleus ipsilateral to the moving hand reversibly increased the reaction time and reduced the size of surface-negative, depth-positive (s-N, d-P) field potential in the motor cortex contralateral to the hand. The potential preceded the movement by an almost constant time of about 100 ms in the normal condition. The cooling remarkably prolonged and deviated the time. By shifting the cooling probe to different distances from the nucleus, we noted various decreases of the cooling effect. We also found a close correlation between the size of the s-N, d-P potential and the reaction time, i.e., when the potential was small, the reaction time was long. These findings support the following ideas; the motor command for this task comes to the motor cortex through the cerebello-thalamo-cortical pathway which includes the dentate nucleus, and produces the s-N, d-P potential as EPSP currents in pyramidal neurons in the motor cortex. We also studied self-paced movement task. In some cases, the cooling reduced the size of readiness potential in the motor cortex.

Monkeys were trained for go/no-go reaction-time hand movement with discrimination between tone stimuli of different frequencies, and field potentials related to the discriminative movement were recorded with electrodes implanted in various cortical areas and analysed by averaging procedure. In the cortex of the dorsal bank of the principal sulcus, surface-negative, depth-positive (s-N, d-P) potentials were recorded specifically on the no-go trial. The same monkey was also examined for go/no-go reaction-time hand movement with color discrimination. In the same monkey, the potentials related to the no-go reaction on the auditory stimulus were recorded in the rostral part of the dorsal bank of the principal sulcus, whereas the s-N, d-P potentials on the no-go visual stimulus were observed in the caudal part of the same bank. It is suggested that the dorsal bank of the principal sulcus is essentially related to the integrative functions such as judgement not to move and suppression of motor execution, and that different loci in this cortical area are respectively active for the functions of different sensory modalities.

Latent time of the hand movement in response to a visual stimulus was found to be very short when a monkey was enough trained with a visual imperative stimulus preceded by a visual warning stimulus at a fixed time interval. Cerebellar hemispherectomy scarcely prolonged the reaction time of the warning-imperative, visually initiated (W-VI) movement in contrast to its marked delaying action upon the simple visually initiated reaction-time (S-VI) movement. Between the warning and imperative stimuli, sustained surface-negative, depth-positive field potentials were recorded in various areas of the prefrontal and premotor cortices and the supplementary motor area of both cerebral hemispheres, besides gradually increasing surface-negative, depth-positive deflections in the motor and somatosensory cortices contralateral to the moving hand. These observations suggest that the sustained activities in the prefrontal and premotor cortices elicited by the warning stimulus overcome deficiency of the cerebellar function for performing fast and stable timing movements.

Monkeys were trained to move the hand in response to imperative visual stimulus (IS) given 1 s after warning visual stimulus (WS). With implanted electrodes in the cortices, surface-negative (s-N), depth-positive (d-P) sustained potentials between WS and IS were recorded in the prefrontal, premotor and supplementary motor areas in both hemispheres, and gradually increasing s-N, d-P potentials were seen in the forelimb areas of motor and somatosensory cortices contralateral to the hand. It is suggested that the sustained and gradually increasing potentials are related respectively to cortical activities associated with expectation and anticipation of the IS, and to those with a preparatory process for the movement. The latter appeared to be similar to the case of self-paced movements. These potentials may correspond respectively to the early and late components of CNV in the human.

Field potentials before vocalization were studied with electrodes chronically implanted on the surface and at a 2.0-3.0 mm depth in various cortical areas in three monkeys. Surface-negative, depth-positive (s-N, d-P) slow potentials prior to vocalization were recorded in the premotor (including the Broca's homolog), motor and somatosensory cortices, and the supplementary motor area (SMA). Such premovement potentials were recorded also in the cingulate and prefrontal cortices when a monkey uttered a sound with intense motivation for reward. Cerebellar hemispherectomy on the right side eliminated the s-N, d-P premovement potentials in the motor cortex and in the posterior bank of inferior limb of the arcuate sulcus (homolog of Broca's area) in the left hemisphere. After the operation, the tone came to have less components of different frequencies, and its duration varied much more than before. These facts suggest that the neocortical area homologous to the human speech area takes part in the generation and control of monkey vocalization together with the cerebellum possibly through cerebro-cerebellar interactions. This is against ideas so far proposed on nonhuman primate vocalization, i.e., it is generally considered that animal vocalization differs fundamentally from human speech.