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Dissociation of Mnemonic Coding and Other Functional Neuronal Processing in the Monkey Prefrontal Cortex SYNNÖVE CARLSON, PIA RÄMÄ, HEIKKI TANILA, ILKKA LINNANKOSKI, AND HEIKKI MANSIKKA Department of Physiology, Institute of Biomedicine, 00014-University of Helsinki, Helsinki, Finland sensory stimulation. These results indicate that most prefrontal neurons firing selectively during the delay phase of the DA task are highly specialized and process only task-related information. INTRODUCTION The importance of the principal sulcus (PS) area in the dorsolateral prefrontal cortex (PFCdl) in spatial short-term mnemonic functions has been well documented in monkeys (for reviews see Fuster 1989; Goldman-Rakic 1987). Lesions in this cortical region produce inability to perform delayed response (DR) tasks (Butters and Pandya 1969; Funahashi et al. 1993a; Goldman 1971; Goldman and Rosvold 1970; Goldman et al. 1971; Jacobsen 1936; Mishkin 1957; Mishkin and Pribram 1955) but do not disrupt the ability to perform various visual discrimination tasks (Fuster 1989; Goldman 1971; Mishkin et al. 1969; Passingham 1972, 1975; Petrides and Iversen 1976). Electrophysiological studies in the PFCdl of monkeys have revealed delay-related neuronal activity during the performance of DR and delayed alternation (DA) tasks in manual (Carlson et al. 1990; Fuster 1973; Fuster and Alexander 1971; Kojima and GoldmanRakic 1984; Kubota and Niki 1971; Niki 1974a–c) and oculomotor (Funahashi et al. 1989–1991; Joseph and Barone 1987) tasks. This delay-related activity exhibits crosstemporal sensory-motor integration including short-term memory and motor preparation (Fuster and Alexander 1971; Fuster et al. 1982; Niki 1974a–c; Quintana et al. 1988). Many neurons in PFCdl have been shown to respond to the visual cue or in relation to the response period of the DR task (e.g., Funahashi et al. 1990; Fuster 1973; Niki 1974c). Neurons changing their firing rate toward the end of the delay period of the task have been suggested to be coupled to preparatory motor activity (Funahashi et al. 1993b; Niki 1974a–c; Niki and Watanabe 1976; Quintana and Fuster 1992). The delay period activity has also been suggested to be related to short-term memory (Fuster 1973; Fuster and Alexander 1971; Kubota and Niki 1971), especially because in a subpopulation of prefrontal neurons the delay-related neuronal activity is spatially selective (Funahashi et al. 1989; Kojima and Goldman-Rakic 1982, 1984; Niki 1974a–c). Furthermore, although many neurons fire in relation to the response period in the oculomotor DR task, the majority of the spatially selective neurons in the PFCdl code the cue location during the delay period rather than the direction of the impending response in an antisaccade task, indicating that the delay activity is related to the remembering of the cue location and not to preparation for a movement (Funahashi et al. 1993b). 0022-3077/97 $5.00 Copyright q 1997 The American Physiological Society / 9k0b$$ja62 J357-6 09-04-97 20:27:27 neupa LP-Neurophys 761 Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 Carlson, Synnöve, Pia Rämä, Heikki Tanila, Ilkka Linnankoski, and Heikki Mansikka. Dissociation of mnemonic coding and other functional neuronal processing in the monkey prefrontal cortex. J. Neurophysiol. 77: 761–774, 1997. Single-neuron activity was recorded in the prefrontal cortex of three monkeys during the performance of a spatial delayed alternation (DA) task and during the presentation of a variety of visual, auditory, and somatosensory stimuli. The aim was to study the relationship between mnemonic neuronal processing and other functional neuronal responsiveness at the single-neuron level in the prefrontal cortex. Recordings were performed in both experimental situations from 152 neurons. The majority of the neurons (92%) was recorded in the prefrontal cortex. Nine of the neurons were recorded in the dorsal bank of the anterior cingulate sulcus and two in the premotor cortex. Of the total number of neurons recorded in the prefrontal area, 32% fired in relation to the DA task performance and 39% were responsive to sensory stimulation or to the movements of the monkey outside of the memory task context. Altogether 42% of the recorded neurons were neither activated by the various stimuli nor by the DA task performance. Three types of task-related neuronal activity were recorded: delay related, delay and movement related, and movement related. The majority of the task-related neurons (n Å 33, 73%) fired in relation to the delay period. Of the delay-related neurons, 26 (79%) were spatially selective. The number of spatially selective delay-related neurons of the whole population of recorded neurons was 18%. Twelve task-related neurons (27%) fired in relation to the response period of the DA task. Five of these neurons changed their firing rate during the delay period and were classified as delay/movement-related neurons. Contrary to the delay-related neurons, less than half (42%) of the responserelated neurons were spatially selective. The majority (70%) of the delay-related neurons could not be activated by any of the sensory stimuli used and did not fire in relation to the movements of the monkey. The remaining portion of the delay-related neurons was activated by stationary and moving visual stimuli or by visual fixation of an object. In contrast to the delay-related neurons, the majority (66%) of the task-related neurons firing in relation to the movement period were also responsive to sensory stimulation outside of the task context. The majority of these neurons responded to visual stimulation, visual fixation of an object, or tracking eye movements. One neuron gave a somatomotor and another a polysensory response. The majority (n Å 37, 67%) of all neurons responding to stimulation outside of the task context did not fire in relation to the DA task performance. The majority of their responses was elicited by visual stimuli or was related to visual fixation of an object or to eye movements. Only six neurons fired in relation to auditory, somatosensory, or somatomotor stimulation. This study provides further evidence about the significance of the dorsolateral prefrontal cortex in spatial working memory processing. Although a considerable number of all DA task-related neurons responded to visual, somatosensory, and auditory stimulation or to the movements of the monkey, most delay-related neurons engaged in the spatial DA task did not respond to extrinsic 762 CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA METHODS Three female monkeys (Macaca arctoides) weighing 6–8 kg were used in the experiment. The animals were housed in individual cages with the other monkeys of the colony. The monkeys were deprived of water during the night preceding the recording day. They were rewarded with juice or water during the recordings, which started in the morning. The monkey’s liquid intake and weight were carefully monitored daily and extra water was given after the experiment, if necessary. The monkey had free access to food. The maintenance of the monkeys and all procedures of the study were carried out according to the Finnish law and statutes governing animal experimentation. The Finnish Ministry of Agriculture had approved of the study and granted permission to perform it. Test panel and DA task performance All monkeys were trained to perform a DA task in three directions: to the right, to the left, and upward. The test panel consisted of a central hold bar and three pairs of response bars that were located on the right and left sides of the hold bar and above it. The test panel was in front of the monkey within the hand’s reach (Fig. 1). The distance between the five horizontally located bars was 12 cm. The lower and upper bars of the vertically oriented pair were 11 and 9 cm above the central hold bar. Above each bar there was a light-emitting diode, which was red above the central bar and green above the response bars. The trial began when the light-emitting diode above the central bar came on and the monkey started to hold it. The monkey was required to hold the central bar continuously throughout the delay period, which was gradually prolonged to 5.3 s during the training period. At the end of the delay, the light-emitting diode above the central bar went off and the green light-emitting diodes above one pair of the response bars turned on. In the first trial, the monkey / 9k0b$$ja62 J357-6 could touch either one of the bars and was rewarded with a drop of juice. In the next trials, only touching the bar of the pair that had not been touched in the previous trial was rewarded. The monkeys were trained until they mastered the task correctly in 80– 100% of daily trials. They were allowed to work daily until they had received juice reward to satiety (300–500 trials per day). Erroneous responses were not rewarded and the trial started from the beginning again. Surgery A stainless steel recording cylinder (diameter 18.7 mm) was implanted onto the skull under general anesthesia (pentobarbital sodium, 25 mg/kg iv). The center of the cylinder was stereotactically aimed at the center of the PS. The stereotaxic coordinates of the centers of the cylinders were A30–A32 and L14–L15 in four hemispheres and A35 and L8 in one hemisphere. In the same operation a halo fixation device was screwed onto the skull. The halo could be attached to the primate chair during the recordings. When the recordings of one hemisphere were completed, the cylinder and the halo were removed and the wound was closed. The cylinder was later implanted on the other hemisphere and the halo was attached. The skin around the cylinder was cleaned daily with iodine detergent, the cylinder was rinsed with sterile saline, and chloramphenicol ocular drops were applied to it. Recording techniques and data analysis Extracellular single-cell activity was recorded with glass-coated tungsten microelectrodes (exposed tips of 20–50 mm, impedances of 0.4–1.5 MV at 1 kHz) with the use of a hydraulic micromanipulator (Narishige MO-9B). With the microdrive coordinate system the penetrations were made at a minimum distance of 1 mm apart from each other. The microdrive coordinates were logged and each penetration was also marked on a chart that was a 10-fold enlargement of the coordinate system. The amplified ( 11,000) and filtered (passband 300–4,000 Hz) neuronal activity was monitored with an oscilloscope, stored on a magnetic tape (Akai GX-630D-SS), and recorded with a pen recorder. The single-cell activity was converted to transistor-transistor logic pulses by a window discriminator. The recording method has been described in detail earlier (Carlson et al. 1990). Horizontal electrooculogram and electromyogram of the triceps brachii muscle were recorded with Ag-AgCl skin electrodes. When the functional responsiveness of the neurons was studied, the cellular activity was also computerized on-line and perievent time rasters and histograms were produced. For this purpose timing pulses of the presentation of visual and auditory stimuli were produced manually and the occurrence of cutaneous stimulation was marked by a probe with an electronic circuitry that produced a signal ( /5 V) when the probe was in contact with the skin of the monkey. Both hemispheres were studied in two monkeys and the left hemisphere was studied in one of the monkeys. Single-cell activity was recorded while the monkey performed the DA task ( Ç20 trials in each of the 3 directions), after which the functional properties of the same neuron were studied. When possible, the basal activity was recorded after the task performance for 60 s. The data recorded during the DA task was analyzed off-line from the stored magnetic tape. Rasters and histograms were produced by aligning the data from different possible triggering points (start of delay, end of delay, receiving of reward). The functional properties of the neurons were studied with a method first introduced by Hyvärinen (1981). The method was later further developed in our laboratory and has been described in detail by Tanila et al. (1992). Furthermore, to provide a homogenous background for the presentation of visual stimuli and to enable more accurate determination of visual receptive fields of neurons, 09-04-97 20:27:27 neupa LP-Neurophys Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 Prefrontal neurons have also been reported to respond to various types of auditory (Azuma and Suzuki 1984; Tanila et al. 1992), visual (Pigarev et al. 1979; Tanila et al. 1992), and multisensory (Tanila et al. 1992; Vaadia et al. 1986; Watanabe 1992) stimuli in monkeys not performing memory tasks. Bimodal responses to both visual and auditory stimulation have been recorded in monkeys (Ito 1982; Vaadia et al. 1986; Watanabe 1992) and in humans (Clarke et al. 1995). Electrophysiological recordings in the prefrontal cortex showed that although many neurons responded to some type of sensory stimulation, almost half (48%) of the recorded neurons remained unresponsive to such stimulation (Tanila et al. 1992). It has been proposed that the neurons in the PFCdl that do not respond to any external stimulation may represent a neuronal population that is engaged in mnemonic processing and other cognitive functions (Tanila et al. 1992). The aim of this work was to study whether, on the singlecell level, there is dissociation between mnemonic coding and other functional neuronal processing, that is, whether or not the same single neurons that are engaged in the DA task performance also respond to various types of visual, auditory, or somatosensory stimuli or to the movements of the monkey. It was hypothesized that neurons that participate in mnemonic functions do not respond to sensory stimulation or in relation to movements outside the task performance, whereas neurons that are not engaged in mnemonic processing are functionally responsive. DISSOCIATION OF FUNCTIONS IN THE PREFRONTAL CORTEX 763 a covered semicircular screen was constructed during the course of the study. The functional properties of the neurons were classified in the following way. 1) Visual/oculomotor: the neuronal response was time locked to the presentation of visual stimuli (stationary or moving objects varying in shape, color, and size) or saccades, to tracking or spontaneous eye movements, or visual fixation of an object. The correlation of the neuronal activity to spontaneous or elicited eye movements was monitored with horizontal electrooculogram and observation of vertical eye movements. 2) Auditory: the response was related to the presentation of auditory stimuli (complex natural sounds varying in pitch and intensity, clicks, rustles, steps, and human voice). 3) Somatosensory: the neurons responded to blowing, light touching, or pinching of the skin and passive movements of the joints. 4) Motor: the neuron fired in relation to movements but not to eye movements per se. The monkey was enticed to reach and grasp objects with its hands and legs and to put pieces of food into its mouth, after which also chewing and licking could be observed. If the neuron responded to more than one type of sensory stimulation it was classified as polysensory. If the neuron did not respond to any of the afore mentioned stimuli it was classified as nonfunctionally responsive (F0 ). / 9k0b$$ja62 J357-6 Statistical analysis The responsiveness of the neurons during different phases of the task performance (delay period, movement period) to the six different target locations was first evaluated visually independently by the investigators. The neurons that were classified as task related (T/ ) or as having a functional response (F/ ) were further analyzed statistically with the use of two-way analysis of variance. Because there is no intertrial period in the DA task (the previous trial is followed immediately by the next trial), the neuronal activity in each trial over all trials to the same target location was studied statistically in the following way. 1) To study the delay period activity, neuronal firing during a 1 or 2-s time period at the beginning of the delay and at the end of the delay were compared. 2) To study the delay/movement-related activity, neuronal firing during a 1 or 2-s time period at the beginning of the delay period was compared with the neuronal activity during a similar time period counted backward from the touching of the target bar (this period consists of the end of the delay and the movement periods). 3) Movement-related neuronal activity was studied for neuronal activity during the time period between the release of the hold bar and touching of the target bar (movement period) and compared 09-04-97 20:27:27 neupa LP-Neurophys Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 FIG . 1. Task-related (T/ ) neuron firing spatially selectively during the delay phase. Each pair of rasters and histograms represents the firing of the neuron in 1 target location. Vertical (V1, V2), left (L1, L2), and right (R1, R2) refer to the locations of the target bars. 1, raster; 2, histogram; 3, receiving of reward; 4, touching the target bar; 5, solid lines indicate the time of holding the central bar. Diagram at right: drawing from the histological coronal section corresponding to the level where the neuron was recorded. Dot: location of the neuron. Diagram at left: test panel. There were significant main effects of the target location [2-way analysis of variance (ANOVA): F(5,84) Å 4.34, P õ 0.005] and the phase of the task [F(1,84) Å 48.87, P õ 0.0001]. This neuron increased its firing significantly during the 1st part of the delay period at R1 [t(16) Å 6.67, P õ 0.0001], R2 [t(16) Å 4.34, P õ 0.001], and V1 [t(16) Å 3.84, P õ 0.005]. 764 CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA TABLE 1. Number and percentage of neurons recorded in different cortical regions in three macaque monkeys Area n Percent 2. Classification of neurons according to their responsiveness to the DA task performance and to stimulation outside of the task context TABLE PFCdl PFCl PFCm PS Cin FEF Pm Total 98 65 1 1 8 5 15 10 9 6 18 12 2 1 151* 100 PFCdl, dorsolateral prefrontal cortex; PFCl, lateral prefrontal cortex; PFCm, medial prefrontal cortex; PS, principal sulcus; Cin, cingulate sulcus; FEF, frontal eye fields; Pm, premotor cortex. *The total number of recorded neurons is 151, instead of 152, because the location of 1 neuron was not identified. Histology At the end of the recording of the first hemisphere, marking electrodes were inserted with the micromanipulator and left in the brain for later verification. At the end of the recordings, anodal direct current (60 mA, 30 s) was passed through the recording electrode to mark a few penetrations. The monkey was killed with an overdose of pentobarbital and the brain was fixed with intracardial perfusion of 0.9% saline followed by 10% Formalin. The brain was photographed. Frozen 30-mm coronal sections were cut and stained with 0.25% cresyl violet. The electrolytic lesions and the tracks of the marking electrodes were identified. The locations of the other penetrations in relation to the marked ones were reconstructed from their microdrive coordinates. For the construction of the brain maps from the histological sections, an average map from the brains of five monkeys (3 monkeys from this study and 2 from an earlier study) was produced according to the method described in an earlier report from this laboratory (Tanila et al. 1993). The recording sites were marked on the map according to their relative location to the PS and arcuate sulcus. The following classification of anatomic locations was used: the PS, areas 46 above the PS and 9 as PFCdl, area 46 below the PS as lateral prefrontal cortex, the medial parts of area 9 as medial prefrontal cortex, the anterior part of the cingulate sulcus, area 8 as frontal eye fields (FEF), and the dorsal part of area 6 as premotor cortex. RESULTS Altogether 152 neurons were studied in three macaque monkeys both during the DA task and for their functional responsiveness. The number of neurons recorded in different regions is shown in Table 1. Nine neurons were recorded in the anterior part of the cingulate sulcus and two neurons were recorded in the premotor cortex. The neuronal responses of these 11 units are described at the end of the RESULTS section. The neurons that showed a distinct pattern of discharge during some phase of the task were classified as T/, and the others were classified as non-task related (T0 ). Same neurons were classified as F/ when they responded to sensory stimulation (visual, auditory, or somatosensory) or when their firing was time locked to the movements of the monkey. If there was no relationship between the neuronal firing and the sensory stimulation and/or the movements of the mon- / 9k0b$$ja62 J357-6 Percent 18 27 37 59 141 12.8 19.2 26.2 41.8 100 DA, delayed alternation; T/, task related; T0, non-task related; F/, functionally responsive; F0, non-functionally responsive. key, the neuron was classified as F0. Altogether 31.9% (45 of 141) of the recorded neurons were classified as T/. Of these T/ neurons, 40.0% (n Å 18) were also F/ (T/F/ ). Thirty-seven (26.2%) neurons were F/ but their firing was not related to the task performance (T0F/ ). Of the total number of recorded neurons, 41.8% were classified as T0F0 neurons (Table 2), which means that the firing of these neurons was related neither to the task performance nor to external stimulation or to the movements of the monkey. T/F/ and T/F0 neurons Of the total number of recorded neurons, 12.8% (n Å 18) were classified as T/F/ neurons, whereas 19.2% (n Å 27) of the neurons were classified as T/F0 neurons (Table 2). Most of the T/F/ neurons gave visual/oculomotor responses (n Å 16, 88.9%). In one neuron, visual/oculomotor response was elicited by stationary stimuli, but in most visual/oculomotor neurons the response was elicited by moving stimuli either in the whole visual field (n Å 4) or in the side contralateral to the recordings (n Å 2). Two neurons responded only when the monkey was presented with a novel stimulus (or a stimulus not used for a while). In seven T/F/ visual/oculomotor neurons the activity was clearly related either to eye movements or to fixation of a visual object. Five of these neurons gave inhibitory responses when the monkey fixated a visual object presented either in the visual field contralateral to the side of the recordings (n Å 1) or anywhere in the visual field (n Å 4). One neuron gave an excitatory response when the monkey fixated a visual object presented anywhere in the visual field. The discharge of one visual/oculomotor neuron was related to moving stimuli and tracking eye movements. Only 2 T/ neurons of 18 responded to other than visual stimulation (Table 3). TABLE 3. Distribution of functional responses of T/ and T0 neurons VisOkm SomMot 88.9 16 5.55 1 T/F/ Percent n T0F/ Percent n 70.3 26 16.2 6 Aud 8.10 3 Poly Total 5.55 1 100 18 5.4 2 100 37 VisOkm, visual/oculomotor; SomMot, somatomotor; Aud, auditory; Poly, polysensory. For other abbreviations, see Table 2. 09-04-97 20:27:27 neupa LP-Neurophys Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 with the neuronal activity of a similar time period at the beginning of the delay period. The main effects of the ‘‘target location’’ and ‘‘phase of the task’’ factors were analyzed. If there was a significant main effect (P õ 0.05) a post hoc analysis was performed (unpaired t-test). For the statistical evaluation of the functional responsiveness of the neurons, the neuronal activity during the presentation of the stimulus over all trials was compared with baseline neuronal activity during a similar time period. T/F/ T/F0 T 0 F/ T 0 F0 Total n DISSOCIATION OF FUNCTIONS IN THE PREFRONTAL CORTEX 765 T/ neurons were further classified according to the phase of the task at which the change in the firing rate occurred. The DA task can be divided into distinct timelocked periods. The trial starts when the monkey starts to hold the central bar. The monkey has to keep in mind the spatial location of the previously touched response bar ( delay period ) . At the end of the delay period the monkey has to stop holding the central bar and touch the response bar ( response period ) . Neurons that showed a distinct pattern of discharge during some phases of the delay period were classified as delay-related neurons ( Fig. 1 ) , whereas neurons firing in relation to the response period were classified as movement-related neurons ( Fig. 2 ) . Neurons that showed a response both during the delay and response periods were classified as delay /movementrelated neurons ( Fig. 3 ) . Cue-related neurons were not involved in the classification because there is no cue period in the DA task as in the DR task. Most of the T/ neurons showed delay-related activity (n Å 33 of 45, 73.3%) that was spatially selective in 26 of 33 neurons (78.8%, Table 4). The mean percentages of movement-related and delay/movement-related neurons were 15.6% (n Å 7) and 11.1% (n Å 5) (Table 4). Of the / 9k0b$$ja62 J357-6 delay-related neurons, 69.7% (n Å 23 of 33) were F0 (Table 5). These neurons make up 16.3% of the total number of neurons recorded (23 of 141 neurons). Those 10 delayrelated neurons that were F/ were all classified as visual/ oculomotor neurons. Two of the visually responsive neurons gave visual responses only when the monkey was presented with a novel stimulus. The four other delay-related visually responsive neurons gave responses to visual stationary stimuli ( n Å 1) or to moving visual stimuli either in the whole visual field (n Å 2) or in the side contralateral to the recording (n Å 1). Four visual/oculomotor neurons gave inhibitory responses when the monkey fixated an object regardless of the direction of gaze (n Å 3) or in the side contralateral to the recording (n Å 1). Contrary to the delay-related neurons, the majority of neurons that fired in relation to the movement period were F/. Of the movement-related and delay/movement-related neurons, 71.4% (n Å 5 of 7) and 60.0% (n Å 3 of 5), respectively, were F/ (Table 5). Three of the movement-related neurons gave visual/oculomotor responses (Fig. 4). Responses to somatomotor (n Å 1) and polysensory (n Å 1) stimulation were also elicited. All delay/movement-related neurons gave responses to visual/oculomotor stimulation. 09-04-97 20:27:27 neupa LP-Neurophys Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 FIG . 2. T/ neuron firing in relation to the movement phase of the task. There were significant main effects of the target location [2-way ANOVA: F(5,106) Å 18.36, P õ 0.0001] and the phase of the task [ F(1,106) Å 146.23, P õ 0.0001]. Although there was significant spatial tuning of the firing of the neuron during the response period [1-way ANOVA: F(5,53) Å 14.20, P õ 0.0001], the firing increased its rate significantly in all target locations [e.g., L2: t(18) Å 4.17, P õ 0.0005]. Other conventions as in Fig. 1. 766 CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA T0F/ and T0F0 neurons The majority of the recorded neurons (n Å 96) did not change their activity in relation to the task performance, and 61.5% of them were defined as F0. Thirty-seven of the T0 neurons were F/ (Table 3). T0F/ neurons were mostly responsive to visual/oculomotor stimulation (n Å 26, 70.3%). Moving visual stimuli (Fig. 5) elicited responses 4. Distribution of T/ neurons into different classes according to their responsiveness during the delay and movement phases of the DA task and their spatial selectiveness in the whole visual field (n Å 6) or in the side contralateral to the recording (n Å 2). The receptive field of one neuron responding to moving stimuli could not be identified. Visual responses were also elicited by stationary stimuli presented anywhere in the visual field (n Å 1) or in the side contralateral to the recording (n Å 1). Two neurons that gave responses in the contralateral side of the recordings responded only to novel stimuli. Four neurons responded to the closing TABLE T/ Total Delay Percent n Motor Percent n D/M Percent n Spatial 73.3 33 78.8 26 15.6 7 28.6 2 11.1 5 60.0 3 Total number of T/ neurons Å 45. D/M, delay/movement-related neurons. For other abbreviations, see Table 2. / 9k0b$$ja62 J357-6 TABLE 5. Classification of different types of T/ neurons according to their responsiveness to stimulation outside of the task context Delay Percent n Motor Percent n D/M Percent n F0 VisOkm 69.7 23 30.3 10 28.6 2 42.9 3 40.0 2 60.0 3 For abbreviations, see Tables 2–4. 09-04-97 20:27:27 neupa LP-Neurophys SomMot 14.3 1 Aud Poly 14.3 1 Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 FIG . 3. T/ neuron firing spatially selectively during the delay and movement phases of the task. There were significant main effects of the target location [2-way ANOVA: F(3,66) Å 11.32, P õ 0.0001] and the phase of the task [ F(1,66) Å 19.35, P õ 0.0001]. The neuron increased its firing rate toward the end of the delay and during the response period of the task at locations R1 [t(12) Å 4.51, P õ 0.001] and R2 [t(18) Å 3.25, P õ 0.005]. Other conventions as in Fig. 1. DISSOCIATION OF FUNCTIONS IN THE PREFRONTAL CORTEX 767 of the eyelids or to changes in illumination in the laboratory (Fig. 6). Seven visual/oculomotor responses were related to visual fixation. The responses were either inhibitory or excitatory to visual stimuli presented anywhere in the visual field (n Å 3) or in the side contralateral to the recordings (n Å 2). The receptive field of two fixation-related neurons could not be identified. Two neurons fired in relation to the presentation of an object or to eye movements toward the object. Neurons in the T0F/ group also responded to somatomotor (n Å 6, 16.2%), auditory (n Å 3, 8.10%, Fig. 7, A and B), or polysensory (n Å 2, 5.4%) stimulation. Somatomotor responses were elicited by the monkey’s own contralateral hand movements (n Å 4), by chewing (n Å 1), or by pressing the midthigh (n Å 1), which gave a response bilaterally. The response was stronger on the contralateral side (Fig. 8). Distribution of the recorded neurons in the prefrontal cortex The distribution of the recorded neurons in different cortical areas is shown in Table 1. Figures 9, A and B, and 10 / 9k0b$$ja62 J357-6 illustrate the regional distribution of T/ and T0 neurons, respectively. Both T0 and T/ neurons were rather evenly distributed over the recorded area. Eighteen neurons were located in the FEF. Seven of these were T/ neurons and three were spatially selective. Two T/ FEF neurons were activated during the movement period of the DA task and the rest were activated during the delay phase. Three of the T/ neurons were also F/ and were classified as visual/ oculomotor. Six other FEF neurons were also F/ but had no relation to the task performance (T0F/ ). Except for one neuron, all other T0F/ neurons in the FEF were responsive to visual/oculomotor stimulation. The one exception was a neuron that fired in relation to the monkey’s hand movement. The sparse auditory responses (3 neurons) were recorded in the anterior parts of the area studied. Of the seven somatomotor neurons, one was located in the inferior bank of the PS, one in the medial prefrontal cortex, four in the prefrontal region above the PS, and one in FEF. Of the four polysensory neurons, one was in the lower bank of the PS, two on the dorsal side of the PS, and one in the premotor cortex. The visually responsive neurons were scattered around the whole recorded area. 09-04-97 20:27:27 neupa LP-Neurophys Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 FIG . 4. Example of a visual/oculomotor neuron responding to the presentation of a visual stimulus at 4 locations in the visual field. The neuron increased its firing rate during the presentation of the visual stimulus. The responses are presented at 4 locations: right [t(16) Å 12.48, P õ 0.0001], left [t(18) Å 6.10, P õ 0.0001], upward [t(18) Å 14.82, P õ 0.0001], and downward [t(18) Å 6.28, P õ 0.0001]. The increased firing was most likely related to visual fixation of an object. Diagram in the middle: drawing from the histological section corresponding to the level at which the neuron was recorded. Dot: location of the neuron. Horizontal lines below the histogram: presentations of the stimulus. 768 CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA Task-related activity and functional responsiveness of cingulate and premotor neurons Nine neurons were located in the upper bank of the anterior part of the cingulate sulcus. Three of these neurons were spatially tuned T/F0 neurons and fired in relation to the delay (1 neuron) or delay/movement phase (2 neurons) of the DA task. Only one cingulate neuron was F/ (T0F/ ) and responded to visual stimulation in the contralateral visual field. The other five T0 neurons were F0. Two neurons (1 FIG . 6. Top histogram: change of illumination elicited a visual response [t(18) Å 5.60, P õ 0.0001]. The lights in the laboratory were turned on and left on at the beginning of the horizontal lines illustrated below the histogram. Bottom histogram: presentation of an visual object did not activate the neuron. The location of the neuron is shown in the diagram at right from the corresponding histological section. / 9k0b$$ja62 J357-6 09-04-97 20:27:27 neupa LP-Neurophys Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 FIG . 5. Example of a neuron responding to the presentation of a visual stimulus moving in depth in front of the monkey [ forward vs. backward motion: t(18) Å 18.41, P õ 0.0001]. Raster and histogram illustrate the firing rate during 10 trials of stimulus presentation. Top histogram: visual stimulus approached the monkey during the period indicated by horizontal bars below the histogram. Bottom histogram: visual stimulus retreated from the monkey. Diagram at top left: drawing from the histological section corresponding to the level where the neuron was recorded. Dot: location of the neuron. DISSOCIATION OF FUNCTIONS IN THE PREFRONTAL CORTEX 769 T0F0 and 1 T/F/ ) were located in the anterior part of the premotor cortex. The T/F/ neuron fired in relation to the movement phase of the DA task. The neuron gave a complex functional response to both visual stimulation and the hand movement of the monkey. DISCUSSION In the present work we studied both functional (motor-related and sensory responsive neurons outside of the task context) and working memory (neurons firing in relation to DA task) properties of single neurons in the prefrontal cortex of macaque monkeys. Of the total number of recorded neurons, 32% fired in relation to the DA task performance, 39% were functionally responsive to sensory stimulation or to the movements of the monkey, and 42% responded neither to the task nor to the various stimulations. Independent of the neuronal discharge during the task performance, the functionally activated neurons were mainly responsive to visual stimulation. The majority (60%) of the neurons firing in relation to the spatial working memory task did not respond to external sensory stimuli or to the movements of the monkey. The two main findings of the present study are the following. 1) The great majority (70%) of the neurons that fired selectively during the delay phase of the DA task could not be activated by any of the various stimuli used in this study. 2) The majority of all F/ neurons did not fire in relation to the working memory task performance and thus possess other than mnemonic functions. / 9k0b$$ja62 J357-6 The delay-related neurons represent the neuronal population that in many previous studies has been suggested to be engaged in the neuronal processing of working memory (for reviews see Funahashi and Kubota 1994; Fuster 1989; Goldman-Rakic 1987, 1995). The present study demonstrates that the majority of these neurons do not process sensory information that is not relevant to the performance of mnemonic tasks. In contrast to the delay-related neurons, 66% of the task specific neurons firing during the movement phase could also be activated by sensory stimulation or movements of the monkey not related to the task context. Neuronal firing during the DA task The present study again demonstrates that there is a population of neurons in the PFCdl that is engaged in the processing of working memory task performance. About a third of the neurons (32%) recorded in this work fired in relation to the DA task. The recordings were conducted mainly in the PFCdl in Walker’s areas 46 and 9 (Walker 1940) extending from the lower lip of PS to the dorsal convexity of the PFCdl (Table 1). Because lesion studies have indicated that the cortex in and around the PS is the most important area for spatial DR and DA performances and lesions sparing this area have little if any effect on such task performance (Goldman and Rosvold 1970; Goldman et al. 1971; Mishkin 1957), most electrophysiological studies concerning spatial working memory processing in the PFCdl have therefore been con- 09-04-97 20:27:27 neupa LP-Neurophys Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 FIG . 7. A: raster and histogram represent the response of a neuron to 11 presentations of an auditory stimulus [t(20) Å 5.22, P õ 0.0001]. The stimulus was a short click presented contralaterally 607 to the right in front of the monkey. The monkey was sitting inside a hemifield, which hindered it from seeing the presentation of the stimulus. B: neuronal firing (1) to 2 presentations of the auditory stimulus (2) illustrated together with the horizontal electrooculogram (3). The firing was not related to eye movements. Other conventions as in Fig 4. 770 CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA FIG . 8. Pressing of the contralateral (A) and ipsilateral (B) midthigh elicited a response [A: t(18) Å 11.58, P õ 0.0001; B: t(18) Å 7.10, P õ 0.0001]. The location of the neuron is shown in the diagram at right from the corresponding histological section. / 9k0b$$ja62 J357-6 Funahashi et al. 1989; Niki 1974a,b). In these studies the number of spatially selective delay-related neurons of all neurons recorded was between 5–18% (Niki 1974a,b) and 24% (Funahashi et al. 1989). Twelve neurons fired in relation to the response period, and five of these changed their firing rate significantly also during the delay period. These neurons were not spatially selective (5 of 12 neurons, 42%) as frequently as the delay neurons. This proportion is smaller than in the study by Funahashi et al. (1991), who reported that 34% of the neurons recorded in the oculomotor DR task changed their firing rate in relation to saccadic eye movements and that ú90% of the neurons were spatially selective. The number of neurons firing in relation to the movement phase in the present work was in the same range (27%). In the present study, the monkeys responded with a hand movement and the results of several studies indicate—although there may be subareal differences in the prefrontal cortex that may have obscured this phenomenon—that the prefrontal cortex has a lower representation of hand-movement-related neurons than of eye-movement-related neurons (Funahashi et al. 1989, 1990, 1993b; Tanila et al. 1992, 1993). It is important to point out that although the horizontal and occasionally the vertical electrooculogram was recorded, the eye movements of the monkeys were not controlled here in the way they were in studies in which oculomotor DR tasks were used (Funahashi et al. 1989–1991) and the task performance did not require the monkey to maintain fixation during the delay period. The movement period thus invariably includes both hand and eye movements because the monkey tends to make a saccade toward the target location just before the hand movement. The movement period related neuronal firing cannot therefore be dissociated from hand and eye movements in this testing paradigm, and, on the basis of the present study, it is not possible to draw conclusions about the motor nature 09-04-97 20:27:27 neupa LP-Neurophys Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 ducted in the dorsal and ventral banks of PS and in the adjacent PFCdl (e.g., Funahashi et al. 1989–1991; Kojima and Goldman-Rakic 1984; Kubota and Niki 1971; Niki 1974a–c). However, electrophysiological studies have also demonstrated delay-related neuronal activity in the prefrontal cortex dorsolateral convexity above PS (Fuster 1973; Quintana et al. 1988), suggesting that prefrontal areas outside PS are also involved in spatial working memory processing. Other prefrontal cortex areas have also recently been shown to be engaged in working memory processing. An electrophysiological study by Wilson et al. (1993) conducted in the ventrolateral prefrontal cortex and a lesion study by Petrides (1995) comprising the mid-dorsal prefrontal cortex indicate that these areas are involved in nonspatial mnemonic processing, suggesting that subareas of the prefrontal cortex are functionally specialized for different aspects of mnemonic processing. The DA task differs from the DR task in several important aspects. The DR task has clearly distinguishable cue, delay, and response periods. The DA task does not have a distinguishable cue period, although it is possible that the monkeys use proprioceptive cues produced by their own movements to solve the task (Gentile and Stamm 1972; Goldman and Rosvold 1970; Wagman 1968), or, in this study, may even have looked at the next correct target because the eye movements were not controlled. Therefore in the DA task one cannot record a cue response in the same sense as in the DR task. The spatial selectiveness of a given neuron can only become evident during the delay and the response period. The majority (73%) of the T/ neurons fired in relation to the delay period and of 79% (26 of 33) of these neurons were spatially selective. The total number of spatially selective delay-related neurons was thus 18%. This finding is in line with earlier reports in which DA or DR tasks have been used to study neuronal activity in the prefrontal cortex (e.g., DISSOCIATION OF FUNCTIONS IN THE PREFRONTAL CORTEX processing and other functional neuronal responsiveness in the prefrontal cortex. For this purpose the monkeys were trained to master a DA task and single-cell responses were recorded during this task performance. The monkeys were also trained to accept another kind of recording situation in which they were presented with various types of stimuli and were not required to respond to them. This experimental situation allowed us to study the responsiveness of single neurons both under a rather strictly controlled behavioral situation and during presentation of a variety of stimuli to the monkey. The majority (70%) of the neurons firing selectively during the delay phase of the DA task did not respond to extrinsic sensory stimulation or to the movements of the monkey. As a comparison, the number of F0 neurons was small among the T/ neurons that fired in relation to the response period: 29% of movement-related and 40% of neurons firing in relation to both the delay and movement phases of the task. This finding is significant because it has been suggested that the delay-related neuronal firing during DR and DA tasks represents mnemonic coding (Fuster 1989; GoldmanRakic 1987, 1995). Funahashi et al. (1990) recorded prefrontal cortex neurons during an oculomotor DR task for several target locations. They also studied some of these neurons during a visuospatial task in which visual stimuli were presented in the same locations as in the oculomotor DR task but the monkey was not required to memorize the stimulus location. Funahashi et al. found that several neurons responded similarly to the cue presentations in both tasks and argued that the responses to cues in the oculomotor DR and visuospatial task reflect the same underlying visual responsiveness of the neuron. The authors suggested that the spatial visual information arriving at the prefrontal neurons is registered in the cuerelated neurons, then fed forward to cue-delay-related neurons that in turn feed the information to delay neurons. The fact that so many of the delay-related neurons of the present study could not be activated by external stimulation is in line with the above suggestion. It is likely that the delay of the movement-related prefrontal cortex neurons during DA task performance. However, in other studies in which manual versions of DR were used (Kojima and GoldmanRakic 1982, 1984; Niki 1974c) or DA tasks (Niki 1974a), the number of movement-related neurons that were spatially selective has been in the same range (45%) (Niki 1974a) as in the present study or even much lower (10–13%) (Kojima and Goldman-Rakic 1982, 1984). Another reason for the high number of spatially selective movement-related neurons recorded in the oculomotor DR task by Funahashi et al. (1989, 1991) is that those researchers used eight target locations, compared with only two or six in the other manual versions of the working memory tasks. Functional responsiveness of DA task-related neurons Our main interest in this work was to study on the singleneuron level the relationship between mnemonic neuronal / 9k0b$$ja62 J357-6 FIG . 10. Regional distribution of non-task-related (T0 ) neurons and their responsiveness to stimulation outside of the task context. Six T0 neurons were located in the anterior cingulate cortex (not illustrated). Five of them were nonfunctionally responsive and 1 responded to visual stimulation. One T0 nonfunctionally responsive neuron was recorded in the premotor cortex (not illustrated). Other conventions as in Fig. 9. 09-04-97 20:27:27 neupa LP-Neurophys Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017 FIG . 9. A: regional distribution of the T/ neurons and their responsiveness outside of the task context. Open circles: non-functionally responsive. V, visual/oculomotor response; S, somatomotor response; A, auditory response; P, polysensory response. The locations of the neurons are projected to the lateral surface of the prefrontal cortex. Three non-functionally responsive T/ neurons were recorded in the anterior cingulate sulcus and 1 functionally responsive neuron (P) was recorded in the premotor cortex (not illustrated). B: areal distribution of the delay-related neurons. White bars: total number of neurons recorded in the corresponding subarea. Black bars: delay-related neurons. 771 772 CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA Functional responsiveness of T0 neurons T0 neurons were responsive to a variety of stimuli: in addition to visual stimuli, responses were elicited by auditory, somatomotor, and polysensory stimuli. Some of the visually responsive neurons were rather ‘‘primitive’’ in their nature. Four neurons responded repetitively to a change in the overall level of illumination (see Fig. 6) or to the covering or uncovering of the eyes. Seven neurons fired in relation to visual fixation of the monkeys. The functional properties of prefrontal cortical neurons have been studied earlier with different types of testing pro- / 9k0b$$ja62 J357-6 cedures and methods. In the study by Pigarev et al. (1979) the monkeys were anesthetized during the recordings. Despite the anesthesia, a variety of visual responses could be recorded in the posterior parts of the prefrontal cortex. Vaadia et al. (1986) recorded neurons in the posterior parts of the prefrontal cortex responding during auditory and visual localization tasks. Ito (1982) used a simple reaction time task with auditory and visual stimuli and found neurons responsive to both types of stimuli. Watanabe (1989) studied neuronal responses during a go/no-go discrimination task and reported that the prefrontal cortex has a role in cognitive functions related to the coding of posttrial events. Watanabe ( 1990) also recorded prefrontal neurons during a stimulusreward association task and found many cue-related responses that were related to the significance of the cue (whether it signaled the receiving of a reward or not) rather than to the physical properties of the cue. In addition to its role in the neuronal processing of spatial working memory, the prefrontal cortex exhibits functional responsiveness to many kinds of visual stimuli and to a lesser extent to somatosensory and auditory stimuli and movements. The majority of the neurons responsive to such stimuli in the present study did not have a role in mnemonic processing and, vice versa, neurons engaged in spatial working memory processing only seldom responded to sensory stimulation that is not relevant to the task performance. Wilson et al. (1993) have recently shown that the inferior convexity in the ventrolateral prefrontal cortex contains neurons responsive to pattern visual stimuli and to faces (Wilson et al. 1993). Many of these visually responsive neurons expressed delay-related activity with selective responsiveness to pattern memoranda, suggesting that the prefrontal cortex contains specialized subareas for the remembering of the spatial location and the identity of visual objects. The recordings in the present study were located more dorsally on the prefrontal cortex than in the above mentioned study, which may explain why complex visual stimuli in our work were not effective in arousing visual responses in most of the delay-related neurons. The results of the present study thus support the idea that the prefrontal cortex is functionally specialized. For fully understanding the behavioral role of the prefrontal cortex, the multiplicity of the functions of the prefrontal cortex needs to be further studied. We thank K. Lauren and P. Kilpiö for technical assistance. This study was supported by The Paulo Foundation, The Finnish Cultural Foundation, and The Kordelin Foundation. Present address of H. Tanila: Dept. of Neuroscience and Neurology, University of Kuopio, Canthia, P.O. Box 1627, 70211 Kuopio, Finland. Address for reprint requests: S. Carlson, Dept. of Physiology, Institute of Biomedicine, P.O. Box 9, 00014-University of Helsinki, Helsinki, Finland. 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