Functional specialization within the dorsolateral frontal cortex for serial order memory.

Monkeys with lesions restricted to two anatomically distinct regions of the dorsolateral frontal cortex were tested on a novel task that was developed to assess memory for the order of occurrence of stimuli. Monkeys with bilateral lesions of the mid-dorsolateral frontal cortex (cytoarchitectonic areas 46 and 9) were severely impaired, whereas monkeys with lesions of the posterior region of the dorsolateral frontal cortex (area 8 and rostral area 6) performed as well as the normal control animals. These results show that the primate mid-dorsolateral frontal cortex is a critical component of a neural circuit underlying the monitoring of the serial order of stimuli.     

The encoding of temporally irregular and regular visual patterns in the human brain

In the work reported here, we set out to study the neural systems that detect predictable temporal patterns and departures from them. We used functional magnetic resonance imaging (fMRI) to locate activity in the brains of subjects when they viewed temporally regular and irregular patterns produced by letters, numbers, colors and luminance. Activity induced by irregular sequences was located within dorsolateral prefrontal cortex, including an area that was responsive to irregular patterns regardless of the type of visual stimuli producing them. Conversely, temporally regular arrangements resulted in activity in the right frontal lobe (medial frontal gyrus), in the left orbito-frontal cortex and in the left pallidum. The results show that there is an abstractive system in the brain for detecting temporal irregularity, regardless of the source producing it.     

额叶冲突加工机制及年老化改变的事件相关电位研究

目的：探讨大脑额叶对冲突信息的加工处理机制及其年老化改变,探索敏感的事件相关电位（ERPs）指标。方法：研究对象为15例正常老年人（老年组）和15例青年成人（青年组）,ERPs检查采用改良的Eriksenflanker视觉刺激范式,记录32导脑电、正确率及反应时。结果：与青年组相比,老年组反应时明显延长,反应阶段干扰效应尤其明显。老年组N380出现时间窗延迟,平均波幅两组无差异,源定位分析（IDRETA）显示青年组可见双颞叶、双前额背外侧区域激活,以右侧明显;老年组主要见左颞叶、左前额背外侧、左前额内侧面区域激活。结论：在反应阶段出现冲突信息时,老年人额叶干扰控制功能减退,差异负波N380与老年人左前额背外侧、左侧颞叶等区域在反应选择、执行控制中的活动有关,且增龄改变明显。     

Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex

The extensive connections of the entorhinal cortex with the hippocampus and the neocortex point to this region as a major interface in the hippocampal-neocortical interactions underlying memory. We asked whether hippocampal-dependent recall of spatial memory depends on the entorhinal cortex, and, if so, which parts are critical. After training in a Morris water maze, rats received fiber-sparing lesions in the dorsolateral band of the entorhinal cortex, which mediates much of the visuospatial input to the dorsal hippocampus. These lesions entirely disrupted retention and retarded new learning. Spatial memory was spared by lesions in the ventromedial band, which connects primarily with ventral hippocampus, but these lesions reduced defensive behavior on an elevated plus maze, mirroring the effects of damage to ventral hippocampus. The results suggest that the functional differences between dorsal and ventral hippocampus reflect their connectivity with modules of the entorhinal cortex that are differently linked to the rest of the cortex.     

Differential Contributions of Dorso-Ventral and Rostro-Caudal Prefrontal White Matter Tracts to Cognitive Control in Healthy Older Adults

Prefrontal cortex mediates cognitive control by means of circuitry organized along dorso-ventral and rostro-caudal axes. Along the dorso-ventral axis, ventrolateral PFC controls semantic information, whereas dorsolateral PFC encodes task rules. Along the rostro-caudal axis, anterior prefrontal cortex encodes complex rules and relationships between stimuli, whereas posterior prefrontal cortex encodes simple relationships between stimuli and behavior. Evidence of these gradients of prefrontal cortex organization has been well documented in fMRI studies, but their functional correlates have not been examined with regard to integrity of underlying white matter tracts. We hypothesized that (a) the integrity of specific white matter tracts is related to cognitive functioning in a manner consistent with the dorso-ventral and rostro-caudal organization of the prefrontal cortex, and (b) this would be particularly evident in healthy older adults. We assessed three cognitive processes that recruit the prefrontal cortex and can distinguish white matter tracts along the dorso-ventral and rostro-caudal dimensions –episodic memory, working memory, and reasoning. Correlations between cognition and fractional anisotropy as well as fiber tractography revealed: (a) Episodic memory was related to ventral prefrontal cortex-thalamo-hippocampal fiber integrity; (b) Working memory was related to integrity of corpus callosum body fibers subserving dorsolateral prefrontal cortex; and (c) Reasoning was related to integrity of corpus callosum body fibers subserving rostral and caudal dorsolateral prefrontal cortex. These findings confirm the ventrolateral prefrontal cortex''s role in semantic control and the dorsolateral prefrontal cortex''s role in rule-based processing, in accordance with the dorso-ventral prefrontal cortex gradient. Reasoning-related rostral and caudal superior frontal white matter may facilitate different levels of task rule complexity. This study is the first to demonstrate dorso-ventral and rostro-caudal prefrontal cortex processing gradients in white matter integrity.     

Prefrontal cortex function, quasi-physiological stimuli, and synaptic plasticity

The prelimbic area of rat medial frontal cortex may be functionally analogous to human/primate dorsolateral prefrontal cortex. This area may be involved in selective attention to the external stimuli and the coupling of the attention to a repertory of actions. It was suggested that this function may rely on a form of long-term memory [Biol. Rev. 77 (2002) 563]. Indeed, during learning of this type of behavior, a portion of prelimbic neurons persistently change their firing characteristics [Prog. Brain Res. 126 (2000) 287]. It is therefore important to study long-term potentiation (LTP) and depression (LTD) in rat prelimbic neurons. In this article, the author first briefly reviews recent findings on the prefrontal cortex function and discusses that the prefrontal cortex may be involved in long-term memory. Second, the author will show some new results which indicate that quasi-physiological patterns of stimuli mimicking prelimbic neuronal activity during behavior can induce LTP in prelimbic pyramidal neuron synapses. These results suggest that prelimbic neuronal activity during behavior may lastingly modify prelimbic synaptic efficacy.     

Control of goal-directed and stimulus-driven attention in the brain

We review evidence for partially segregated networks of brain areas that carry out different attentional functions. One system, which includes parts of the intraparietal cortex and superior frontal cortex, is involved in preparing and applying goal-directed (top-down) selection for stimuli and responses. This system is also modulated by the detection of stimuli. The other system, which includes the temporoparietal cortex and inferior frontal cortex, and is largely lateralized to the right hemisphere, is not involved in top-down selection. Instead, this system is specialized for the detection of behaviourally relevant stimuli, particularly when they are salient or unexpected. This ventral frontoparietal network works as a 'circuit breaker' for the dorsal system, directing attention to salient events. Both attentional systems interact during normal vision, and both are disrupted in unilateral spatial neglect.     

Neuronal correlates of metacognition in primate frontal cortex

Humans are metacognitive: they monitor and control their cognition. Our hypothesis was that neuronal correlates of metacognition reside in the same brain areas responsible for cognition, including frontal cortex. Recent work demonstrated that nonhuman primates are capable of metacognition, so we recorded from single neurons in the frontal eye field, dorsolateral prefrontal cortex, and supplementary eye field of monkeys (Macaca mulatta) that performed a metacognitive visual-oculomotor task. The animals made a decision and reported it with a saccade, but received no immediate reward or feedback. Instead, they had to monitor their decision and bet whether it was correct. Activity was correlated with decisions and bets in all three brain areas, but putative metacognitive activity that linked decisions to appropriate bets occurred exclusively in the SEF. Our results offer a survey of neuronal correlates of metacognition and implicate the SEF in linking cognitive functions over short periods of time.     

Memory trace in prefrontal cortex: theory for the cognitive switch

The dorsolateral prefrontal cortex in human and non-human primates functions as the highest-order executor for the perception-action cycle. According to this view, when perceptual stimuli from the environment are novel or complex, the dorsolateral prefrontal cortex serves to set consciously a goal-directed scheme which broadly determines an action repertory to meet the particular demand from the environment. In this respect, the dorsolateral prefrontal cortex is a short-term activation device with the properties of a cognitive switch', because it couples a particular set of perceptual stimuli to a particular set of actions. Here, I suggest that, in order for the organism to react systematically to the environment, neural traces for the switch function must be stored in the brain. Thus, the highest-order, perception-action interface function of the dorsolateral prefrontal cortex per se depends on permanently stored neural traces in the dorsolateral prefrontal cortex and related structures. Such a memory system may be located functionally between two of the well-documented memory systems in the brain: the declarative memory system and the procedural memory system. Finally, based on available neurophysiological data, the possible mechanisms underlying the formation of cognitive switch traces are proposed.     

Activation of brain structures by fMRI data when viewing the video clips and recall of shown actions

In 10 healthy volunteers, brain tomograms were recorded using an fMRI scanner with a 3T-field magnet. Emotionally neutral and emotionally involving videos were used for stimulation. Registration consisted of seven series: two series of viewing a fixation point and two kinds of video clips, one series of viewing of a succession of two types of video clips, two series of watching videos with subsequent recall, and two series of viewing the fixation point followed by recall of content online. Viewing content online caused the greatest degree of metabolism increase localized in the visual cortex. This activation was more pronounced during the presentation of an emotionally involving video clip. In addition to the occipital lobe, it actively involved the temporal, parietal and, to a lesser extent, the frontal cortex. Activation of the motor cortex was detected only in some subjects. The "interference" effect in which the increase in metabolism was minimal was observed during a consequent demonstration of video-clips. Immediate recall of video-clips after viewing caused the greatest activation of the posterior frontal and motor cortex. Delayed recall activated mostly the anterior frontal cortex. There was a decrease of metabolism in the visual cortex during the recall. The greatest reduction in the visual cortex was observed during immediate recall. Immediate and delayed recall activated the structures associated with the maintenance of consciousness, memory and a system of mirror neurons.     

Response inhibition during cue reactivity in problem gamblers: an fMRI study

Disinhibition over drug use, enhanced salience of drug use and decreased salience of natural reinforcers are thought to play an important role substance dependence. Whether this is also true for pathological gambling is unclear. To understand the effects of affective stimuli on response inhibition in problem gamblers (PRGs), we designed an affective Go/Nogo to examine the interaction between response inhibition and salience attribution in 16 PRGs and 15 healthy controls (HCs).Four affective blocks were presented with Go trials containing neutral, gamble, positive or negative affective pictures. The No-Go trials in these blocks contained neutral pictures. Outcomes of interest included percentage of impulsive errors and mean reaction times in the different blocks. Brain activity related to No-Go trials was assessed to measure response inhibition in the various affective conditions and brain activity related to Go trials was assessed to measure salience attribution.PRGs made fewer errors during gamble and positive trials than HCs, but were slower during all trials types. Compared to HCs, PRGs activated the dorsolateral prefrontal cortex, anterior cingulate and ventral striatum to a greater extent while viewing gamble pictures. The dorsal lateral and inferior frontal cortex were more activated in PRGs than in HCs while viewing positive and negative pictures. During neutral inhibition, PRGs were slower but similar in accuracy to HCs, and showed more dorsolateral prefrontal and anterior cingulate cortex activity. In contrast, during gamble and positive pictures PRGs performed better than HCs, and showed lower activation of the dorsolateral and anterior cingulate cortex.This study shows that gambling-related stimuli are more salient for PRGs than for HCs. PRGs seem to rely on compensatory brain activity to achieve similar performance during neutral response inhibition. A gambling-related or positive context appears to facilitate response inhibition as indicated by lower brain activity and fewer behavioural errors in PRGs.     

A frontal variant of Alzheimer's disease exhibits decreased calcium-independent phospholipase A2 activity in the prefrontal cortex

A frontal variant of Alzheimer's disease (AD) has recently been identified on neuropathological and neuropsychological grounds (Johnson, J.K., Head, E., Kim, R., Starr, A., Cotman, C.W., 1999. Clinical and pathological evidence for a frontal variant of Alzheimer Disease. Arch. Neurol. 56, 1233-1239). Frontal AD differs strikingly from typical AD by the occurrence of neurofibrillary tangle densities in the frontal cortex as high or higher than in the entorhinal cortex. Since cerebrocortical membranes are commonly abnormal in Alzheimer's disease (AD), we assayed frontal AD cases for enzymes regulating membrane phospholipid composition. We specifically measured activity of phospholipase A2s (PLA2s) in dorsolateral prefrontal and lateral temporal cortices of frontal AD cases (n=12), which have respectively high and low densities of neurofibrillary tangles. In neither cortical area was Ca(2+)-dependent PLA2 activity abnormal compared to controls (n=12). In contrast, a significant 42% decrease in Ca(2+)-independent PLA2 activity was found in the dorsolateral prefrontal, but not the lateral temporal, cortex of the frontal AD cases. Similarly, the dorsolateral prefrontal cortex, but not the lateral temporal cortex of the frontal AD cases suffered a 42% decrease in total free fatty acid content, though neither that decrease nor those in any one species of free fatty acid was significant. The observed biochemical changes probably occurred in neurons given (a) our finding that PLA2 activity of cultured human NT2 neurons is virtually all Ca(2+)-independent and (b) the finding of others that nearly all Ca(2+)-independent PLA2 in brain gray matter is neuronal. The decrease in Ca(2+)-independent PLA2 activity is not readily attributable to Group VI or VIII iPLA2s since neither NT2N neurons nor our brain homogenates were greatly inhibited by drugs potently suppressing those iPLA2s. Decreased Ca(2+)-independent PLA2 activity in frontal AD may reflect a compensatory response to pathologically accelerated phospholipid metabolism early in the disorder. That could cause an early elevation of prefrontal free fatty acids, which can stimulate polymerization of tau and thus promote the prefrontal neurofibrillary tangle formation characteristic of frontal AD.     

A neural network reflecting decisions about human faces.

Anatomic structures have been linked to the mnemonic component of working memory, but the neural network underlying associated decision processes remains elusive. Here we present an event-related functional magnetic resonance imaging study that measured activity during the decision period of a delayed face recognition task. A double dissociation of activity between anterior cingulate cortex (ACC), and a network including left fusiform face area (FFA) and left dorsolateral prefrontal cortex (DLPFC), reflected whether a probe face matched the remembered face at the time of decision. Greater activity in the left FFA and left DLPFC correlated with probe faces that matched the remembered face; in contrast, activity in ACC was greater when the probe face did not match the remembered face. These results support a model where frontal regions act in concert with stimulus-specific temporal structures to make recognition decisions about visual stimuli.     

Neural structures associated with recognition of facial expressions of basic emotions.

People with Huntington''s disease and people suffering from obsessive compulsive disorder show severe deficits in recognizing facial expressions of disgust, whereas people with lesions restricted to the amygdala are especially impaired in recognizing facial expressions of fear. This double dissociation implies that recognition of certain basic emotions may be associated with distinct and non-overlapping neural substrates. Some authors, however, emphasize the general importance of the ventral parts of the frontal cortex in emotion recognition, regardless of the emotion being recognized. In this study, we used functional magnetic resonance imaging to locate neural structures that are critical for recognition of facial expressions of basic emotions by investigating cerebral activation of six healthy adults performing a gender discrimination task on images of faces expressing disgust, fear and anger. Activation in response to these faces was compared with that for faces showing neutral expressions. Disgusted facial expressions activated the right putamen and the left insula cortex, whereas enhanced activity in the posterior part of the right gyrus cinguli and the medial temporal gyrus of the left hemisphere was observed during processing of angry faces. Fearful expressions activated the right fusiform gyrus and the left dorsolateral frontal cortex. For all three emotions investigated, we also found activation of the inferior part of the left frontal cortex (Brodmann area 47). These results support the hypotheses derived from neuropsychological findings, that (i) recognition of disgust, fear and anger is based on separate neural systems, and that (ii) the output of these systems converges on frontal regions for further information processing.     

Neonatal cerebral cortical lesion abolishes the anxiolytic action of diazepam in adult rats: effects of location and extent of cortical lesion.

In our previous study, diazepam (DZP), a benzodiazepine receptor agonist, failed to suppress foot-shock-elicited ultrasonic vocalizations (USVs) in adult rats that had been neonatally lesioned in the neocortex. Because neonatal lesion of the neocortex did not influence the production of USVs, the presence of an anxiolytic mechanism of DZP is suggested apart from any anxiogenic mechanism in the brain. However, the previous study did not indicate any specific cortical regional lesions that impaired the normal development of the anxiolytic mechanism in the brain. The present study was undertaken in order to examine whether neonatal lesion of the neocortex, smaller and more localized than that in the previous study, abolishes the anxiolytic effect of DZP on foot-shock-elicited and air-puff-elicited USVs. A neonatal lesion about 2 mm diameter was made in the unilateral frontal cortex frontal to the hindlimb area or in the occipital cortex caudal to the hindlimb area. The attenuating effect of DZP on the USVs elicited by both aversive stimuli was found to be abolished only in the frontal cortex-lesioned rats. This finding indicates that the frontal cortex is likely to be specifically involved in the normal development of the benzodiazepine-anxiolytic mechanism in the brain.     

Role of Medio-Dorsal Frontal and Posterior Parietal Neurons during Auditory Detection Performance in Rats

To further characterize the role of frontal and parietal cortices in rat cognition, we recorded action potentials simultaneously from multiple sites in the medio-dorsal frontal cortex and posterior parietal cortex of rats while they performed a two-choice auditory detection task. We quantified neural correlates of task performance, including response movements, perception of a target tone, and the differentiation between stimuli with distinct features (different pitches or durations). A minority of units—15% in frontal cortex, 23% in parietal cortex—significantly distinguished hit trials (successful detections, response movement to the right) from correct rejection trials (correct leftward response to the absence of the target tone). Estimating the contribution of movement-related activity to these responses suggested that more than half of these units were likely signaling correct perception of the auditory target, rather than merely movement direction. In addition, we found a smaller and mostly not overlapping population of units that differentiated stimuli based on task-irrelevant details. The detection-related spiking responses we observed suggest that correlates of perception in the rat are sparsely represented among neurons in the rat''s frontal-parietal network, without being concentrated preferentially in frontal or parietal areas.     

Neural Mechanism of Facilitation System during Physical Fatigue

An enhanced facilitation system caused by motivational input plays an important role in supporting performance during physical fatigue. We tried to clarify the neural mechanisms of the facilitation system during physical fatigue using magnetoencephalography (MEG) and a classical conditioning technique. Twelve right-handed volunteers participated in this study. Participants underwent MEG recording during the imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The metronome sounds were used as conditioned stimuli and maximum handgrip trials as unconditioned stimuli. The next day, they were randomly assigned to two groups in a single-blinded, two-crossover fashion to undergo two types of MEG recordings, that is, for the control and motivation sessions, during the imagery of maximum grips of the right hand guided by metronome sounds for 10 min. The alpha-band event-related desynchronizations (ERDs) of the motivation session relative to the control session within the time windows of 500 to 700 and 800 to 900 ms after the onset of handgrip cue sounds were identified in the sensorimotor areas. In addition, the alpha-band ERD within the time window of 400 to 500 ms was identified in the right dorsolateral prefrontal cortex (Brodmann''s area 46). The ERD level in the right dorsolateral prefrontal cortex was positively associated with that in the sensorimotor areas within the time window of 500 to 700 ms. These results suggest that the right dorsolateral prefrontal cortex is involved in the neural substrates of the facilitation system and activates the sensorimotor areas during physical fatigue.     

Attentional set-shifting deficit in Parkinson's disease is associated with prefrontal dysfunction: an FDG-PET study

The attentional set-shifting deficit that has been observed in Parkinson's disease (PD) has long been considered neuropsychological evidence of the involvement of meso-prefrontal and prefrontal-striatal circuits in cognitive flexibility. However, recent studies have suggested that non-dopaminergic, posterior cortical pathologies may also contribute to this deficit. Although several neuroimaging studies have addressed this issue, the results of these studies were confounded by the use of tasks that required other cognitive processes in addition to set-shifting, such as rule learning and working memory. In this study, we attempted to identify the neural correlates of the attentional set-shifting deficit in PD using a compound letter task and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography during rest. Shift cost, which is a measure of attentional set-shifting ability, was significantly correlated with hypometabolism in the right dorsolateral prefrontal cortex, including the putative human frontal eye field. Our results provide direct evidence that dysfunction in the dorsolateral prefrontal cortex makes a primary contribution to the attentional set-shifting deficit that has been observed in PD patients.     

Strength of response suppression to distracter stimuli determines attentional-filtering performance in primate prefrontal neurons

Neurons in the primate dorsolateral prefrontal cortex (dlPFC) filter attended [corrected] targets distinctly from distracters through their response rates. The extent to which this ability correlates with the organism's performance, and the neural processes underlying it, remain unclear. We trained monkeys to attend to a visual target that differed in rank along a color-ordinal scale from that of a distracter. The animals' performance at focusing attention on the target and filtering out the distracter improved as ordinal distance between the stimuli increased. Importantly, dlPFC neurons also improved their filtering performance with increasing ordinal target-distracter distance; they built up their response rate in anticipation of the target-distracter onset, and then units encoding target representations increased their firing rate by similar amounts, whereas units encoding distracter representations gradually suppressed their rates as the interstimulus ordinal distance increased. These results suggest that attentional-filtering performance in primates relies upon dlPFC neurons' ability to suppress distracter representations.     

Role of the frontal cortex in organizing emotional-behavioral reactions induced by hypothalamic stimulation and natural stimuli

Study of the effects of a functional switching off the sensorimotor neocortex area in cats by means of cooling reveals its inhibitory influence on emotional-behavioral reactions to hypothalamic stimulation. Multiple (up to 12) switchings off of the frontal neocortex are attended with a gradual compensation of its inhibitory function by the activity of other brain structures. On the other hand inactivation of the sensorimotor cortex reduces the ability of natural provoking stimuli to lower the thresholds of goal-directed rage which develops when these stimuli are combined with an electrical stimulation of the hypothalamus. A conclusion has been made on the participation of the frontal neocortex in the systemic organization of estimation of biologically significant stimuli.