The cognit: a network model of cortical representation.

The prevalent concept in modular models is that there are discrete cortical domains dedicated more or less exclusively to such cognitive functions as visual discrimination, language, spatial attention, face recognition, motor programming, memory retrieval, and working memory. Most of these models have failed or languished for lack of conclusive evidence. In their stead, network models are emerging as more suitable and productive alternatives. Network models are predicated on the basic tenet that cognitive representations consist of widely distributed networks of cortical neurons. Cognitive functions, namely perception, attention, memory, language, and intelligence, consist of neural transactions within and between these networks. The present model postulates that memory and knowledge are represented by distributed, interactive, and overlapping networks of neurons in association cortex. Such networks, named cognits, constitute the basic units of memory or knowledge. The association cortex of posterior-post-rolandic-regions contains perceptual cognits: cognitive networks made of neurons associated by information acquired through the senses. Conversely, frontal association cortex contains executive cognits, made of neurons associated by information related to action. In both posterior and frontal cortex, cognits are hierarchically organized. At the bottom of that organization-that is, in parasensory and premotor cortex-cognits are small and relatively simple, representing simple percepts or motor acts. At the top of the organization-in temporo-parietal and prefrontal cortex-cognits are wider and represent complex and abstract information of perceptual or executive character. Posterior and frontal networks are associated by long reciprocal cortico-cortical connections. These connections support the dynamics of the perception-action cycle in sequential behavior, speech, and reasoning.     

Cortical dynamics of memory.

Memory networks are formed in the cerebral cortex by associative processes, following Hebbian principles of synaptic modulation. Sensory and motor memory networks are made of elementary representations in cell assemblies of primary sensory and motor cortex (phyletic memory). Higher-order individual memories, e.g. episodic, semantic, conceptual - are represented in hierarchically organized neuronal networks of the cortex of association. Perceptual memories are organized in posterior (post-rolandic) cortex, motor (executive) memories in cortex of the frontal lobe. Memory networks overlap and interact profusely with one another, such that a cellular assembly can be part of many memories or networks. Working memory essentially consists in the temporary activation of a memory network, as needed for the execution of successive acts in a temporal structure of behavior. That activation of the network is maintained by recurrent excitation through reentrant circuits. The recurrent reentry may occur within local circuits as well as between separate cortical areas. In either case. recurrence binds together the associated components of the network and thus of the memory it represents.     

Frontal lobe and cognitive development

In phylogeny as in ontogeny, the association cortex of the frontal lobe, also known as the prefrontal cortex, is a late-developing region of the neocortex. It is also one of the cortical regions to undergo the greatest expansion in the course of both evolution and individual maturation. In the human adult, the prefrontal cortex constitutes as much as nearly one-third of the totality of the neocortex. The protracted, relatively large, development of the prefrontal cortex is manifest in gross morphology as well as fine structure. In the developing individual, its late maturation is made most apparent by the late myelination of its axonal connections. This and other indices of morphological development of the prefrontal cortex correlate with the development of cognitive functions that neuropsychological studies in animals and humans have ascribed to this cortex. In broad outline, the ventromedial areas of the prefrontal cortex, which with respect to otherprefrontal areas develop relatively early, are involved in the expression and control of emotional and instinctual behaviors. On the other hand, the late maturing areas of the lateral prefrontal convexity are principally involved in higher executive functions. The most general executive function of the lateral prefrontal cortex is the temporal organization of goal-directed actions in the domains of behavior, cognition, and language. In all three domains, that global function is supported by a fundamental role of the lateral prefrontal cortex in temporal integration, that is, the integration of temporally discontinuous percepts and neural inputs into coherent structures of action. Temporal integration is in turn served by at least three cognitive functions of somewhat different prefrontal topography: working memory, preparatory set, and inhibitory control. These functions engage the prefrontal cortex in interactive cooperation with other neocortical regions. The development of language epitomizes the development of temporal integrative cognitive functions and their underlying neural substrate, notably the lateral prefrontal cortex and other late-developing cortical regions.     

Jackson and the frontal executive hierarchy.

Executive actions are represented and hierarchically organized in the cortex of the frontal lobe. The representation and coordination of an action or series of actions have the same anatomical substrate: an executive neuronal network (cognit) in forntal cortex. That network interacts structurally and dynamically with perceptual networks of posterior cortex at the highest levels of the perception-action cycle.     

Brain atrophy associated with baseline and longitudinal measures of cognition

The overall goal was to identify patterns of brain atrophy associated with cognitive impairment and future cognitive decline in non-demented elders. Seventy-one participants were studied with structural MRI and neuropsychological testing at baseline and 1-year follow-up. Deformation-based morphometry was used to examine the relationship between regional baseline brain tissue volume with baseline and longitudinal measures of delayed verbal memory, semantic memory, and executive function. Smaller right hippocampal and entorhinal cortex (ERC) volumes at baseline were associated with worse delayed verbal memory performance at baseline while smaller left ERC volume was associated with greater longitudinal decline. Smaller left superior temporal cortex at baseline was associated with worse semantic memory at baseline, while smaller left temporal white and gray matter volumes were associated with greater semantic memory decline. Increased CSF and smaller frontal lobe volumes were associated with impaired executive function at baseline and greater longitudinal executive decline. These findings suggest that baseline volumes of prefrontal and temporal regions may underlie continuing cognitive decline due to aging, pathology, or both in non-demented elderly individuals.     

Neuroanatomical and cognitive mediators of age-related differences in episodic memory

Aging is associated with declines in episodic memory. In this study, the authors used a path analysis framework to explore the mediating role of differences in brain structure, executive functions, and processing speed in age-related differences in episodic memory. Measures of regional brain volume (prefrontal gray and white matter, caudate, hippocampus, visual cortex), executive functions (working memory, inhibitory control, task switching, temporal processing), processing speed, and episodic memory were obtained in a sample of young and older adults. As expected, age was linked to reduction in regional brain volumes and cognitive performance. Moreover, neural and cognitive factors completely mediated age differences in episodic memory. Whereas hippocampal shrinkage directly affected episodic memory, prefrontal volumetric reductions influenced episodic memory via limitations in working memory and inhibitory control. Age-related slowing predicted reduced efficiency in temporal processing, working memory, and inhibitory control. Lastly, poorer temporal processing directly affected episodic memory. No direct effects of age on episodic memory remained once these factors were taken into account. These analyses highlight the value of a multivariate approach with the understanding of complex relationships in cognitive and brain aging.     

Effects of chewing in working memory processing

It has been generally suggested that chewing produces an enhancing effect on cognitive performance-related aspects of memory by the test battery. Furthermore, recent studies have shown that chewing is associated with activation of various brain regions, including the prefrontal cortex. However, little is known about the relation between cognitive performances affected by chewing and the neuronal activity in specified regions in the brain. We therefore examined the effects of chewing on neuronal activities in the brain during a working memory task using fMRI. The subjects chewed gum, without odor and taste components, between continuously performed two- or three-back (n-back) working memory tasks. Chewing increased the BOLD signals in the middle frontal gyrus (Brodmann's areas 9 and 46) in the dorsolateral prefrontal cortex during the n-back tasks. Furthermore, there were more prominent activations in the right premotor cortex, precuneus, thalamus, hippocampus and inferior parietal lobe during the n-back tasks after the chewing trial. These results suggest that chewing may accelerate or recover the process of working memory besides inducing improvement in the arousal level by the chewing motion.     

The role of stimulus type in age-related changes of visual working memory

Aging is accompanied by increasing difficulty in working memory associated with the temporary storage and processing of goal-relevant information. Face recognition plays a preponderant role in human behavior, and one might therefore suggest that working memory for faces is spared from age-related decline compared to socially less important visual stimulus material. To test this hypothesis, we performed working memory (n-back) tasks with two different visual stimulus types, namely faces and doors, and compared them to tasks with primarily verbal material, namely letters. Age-related reaction time slowing was comparable for all three stimulus types, supporting hypotheses on general cognitive and motor slowing. In contrast, performance substantially declined with age for faces and doors, but little for letters. Working memory for faces resulted in significantly better performance than that for doors and was more sensitive to on-line manipulation errors such as the temporal order. All together, our results show that even though face perception might play a specific role in visual processing, visual working memory for faces undergoes the same age-related decline as it does for socially less relevant visual material. Moreover, these results suggest that working memory decline cannot be solely explained by increasing vulnerability in prefrontal cortex related to executive functioning, but indicate an age-related decrease in a visual short-term buffer, possibly located in the temporal cortex.     

Functional modularity of the medial prefrontal cortex: involvement in human empathy

To investigate medial frontal lobe mediation of human empathy, the authors analyzed the activation areas in statistical parametric maps of 80 studies reporting neural correlates of empathic processing. The meta-analysis revealed 6 spatially distinct activation clusters in the medial part of the frontal lobe dorsal to the intercommissural plane. The most dorsal cluster coincided with the left supplementary motor area (SMA). Rostrally adjacent was a cluster that overlapped with the right pre-SMA. In addition, there were 3 left-hemispheric and 1 right-hemispheric clusters located at the border between the superior frontal and anterior cingulate gyrus. A broad spectrum of cognitive functions were associated with these clusters, including attention to one's own action, which was related to activations in the SMA, and valuation of other people's behavior and ethical categories, which was related to activations in the most rostroventral cluster. These data complement the consistent observation that lesions of the medial prefrontal cortex interfere with a patient's perception of own bodily state, emotional judgments, and spontaneous behavior. The results of the current meta-analysis suggest the medial prefrontal cortex mediates human empathy by virtue of a number of distinctive processing nodes. In this way, the authors' findings suggest differentiated aspects of self-control of behavior.     

Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia

Perinatal brain injury including white matter damage (WMD) is highly related to sensory, motor or cognitive impairments in humans born prematurely. Our aim was to examine the neuroanatomical, functional and behavioral changes in adult rats that experienced prenatal ischemia (PI), thereby inducing WMD. PI was induced by unilateral uterine artery ligation at E17 in pregnant rats. We assessed performances in gait, cognitive abilities and topographical organization of maps, and neuronal and glial density in primary motor and somatosensory cortices, the hippocampus and prefrontal cortex, as well as axonal degeneration and astrogliosis in white matter tracts. We found WMD in corpus callosum and brainstem, and associated with the hippocampus and somatosensory cortex, but not the motor cortex after PI. PI rats exhibited mild locomotor impairments associated with minor signs of spasticity. Motor map organization and neuronal density were normal in PI rats, contrasting with major somatosensory map disorganization, reduced neuronal density, and a marked reduction of inhibitory interneurons. PI rats exhibited spontaneous hyperactivity in open-field test and short-term memory deficits associated with abnormal neuronal density in related brain areas. Thus, this model reproduces in adult PI rats the main deficits observed in infants with a perinatal history of hypoxia-ischemia and WMD.     

Executive functions and neurocognitive aging: dissociable patterns of brain activity

Studies of neurocognitive aging report altered patterns of brain activity in older versus younger adults performing executive function tasks. We review the extant literature, using activation likelihood estimation meta-analytic methods, to compare age-related differences in the pattern of brain activity across studies examining 2 categories of tasks associated with executive control processing: working memory and inhibition. In a direct contrast of young and older adult activations, older adults engaged bilateral regions of dorsolateral prefrontal cortex as well as supplementary motor cortex and left inferior parietal lobule during working memory. In contrast, age-related changes during inhibitory control were observed in right inferior frontal gyrus and presupplementary motor area. Additionally, when we examined task-related differences within each age group we observed the predicted pattern of differentiated neural response in the younger subjects: lateral prefrontal cortex activity associated with working memory versus right anterior insula/frontal opercular activity associated with inhibition. This separation was largely maintained in older subjects. These data provide the first quantitative meta-analytic evidence that age-related patterns of functional brain change during executive functioning depend on the specific control process being challenged.     

Persistent working memory dysfunction following traumatic brain injury: Evidence for a time-dependent mechanism

The prefrontal cortex is highly vulnerable to traumatic brain injury (TBI) resulting in the dysfunction of many high-level cognitive and executive functions such as planning, information processing speed, language, memory, attention, and perception. All of these processes require some degree of working memory. Interestingly, in many cases, post-injury working memory deficits can arise in the absence of overt damage to the prefrontal cortex. Recently, excess GABA-mediated inhibition of prefrontal neuronal activity has been identified as a contributor to working memory dysfunction within the first month following cortical impact injury of rats. However, it has not been examined if these working memory deficits persist, and if so, whether they remain amenable to treatment by GABA antagonism. Our findings show that working memory dysfunction, assessed using both the delay match-to-place and delayed alternation T-maze tasks, following lateral cortical impact injury persists for at least 16 weeks post-injury. These deficits were found to be no longer the direct result of excess GABA-mediated inhibition of medial prefrontal cortex neuronal activity. Golgi staining of prelimbic pyramidal neurons revealed that TBI causes a significant shortening of layers V/VI basal dendrite arbors by 4 months post-injury, as well as an increase in the density of both basal and apical spines in these neurons. These changes were not observed in animals 14 days post-injury, a time point at which administration of GABA receptor antagonists improves working memory function. Taken together, the present findings, along with previously published reports, suggest that temporal considerations must be taken into account when designing mechanism-based therapies to improve working memory function in TBI patients.     

Working memory performance in typically developing children and adolescents: behavioral evidence of protracted frontal lobe development

Post-mortem histological and in vivo neuroimaging findings both reveal frontal lobe development that extends beyond the adolescent years. Few studies have examined whether this protracted neurodevelopment coincides with improvements in adolescent performance on putative frontal lobe tasks. An instrumental function supported by the frontal lobes is working memory, the ability to maintain and manipulate information online. This study investigated the performance of typically developing children and adolescents on a battery of working memory tasks. Findings revealed an improvement in performance on most working memory tasks across the adolescent years. In contrast, no improvement was observed on tasks largely supported by more posterior neural substrates. Current findings indicate a similar unfolding of the executive aspects of verbal working memory as previously demonstrated with spatial working memory. Factor analysis revealed a grouping of working memory tasks based largely on task demands, irrespective of working memory domain, adding support for process-specific models of prefrontal organization. Important implications for typical and atypical frontal lobe development are discussed.     

The functional neuroanatomy of working memory: contributions of human brain lesion studies

Studies of patients with focal brain lesions remain critical components of research programs attempting to understand human brain function. Whereas functional imaging typically reveals activity in distributed brain regions that are involved in a task, lesion studies can define which of these brain regions are necessary for a cognitive process. Further, lesion studies are less critical regarding the selection of baseline conditions needed in functional brain imaging research. Lesion studies suggest a functional subdivision of the visuospatial sketchpad of working memory with a ventral stream reaching from occipital to temporal cortex supporting object recognition and a dorsal stream connecting the occipital with parietal cortex enabling spatial operations. The phonological loop can be divided into a phonological short-term store in inferior parietal cortex and an articulatory subvocal rehearsal process relying on brain areas necessary for speech production, i.e. Broca's area, the supplementary motor association area and possibly the cerebellum. More uncertainty exists regarding the role of the prefrontal cortex in working memory. Whereas single cell studies in non-human primates and functional imaging studies in humans have suggested an extension of the ventral and dorsal path into different subregions of the prefrontal cortex, lesion studies together with recent single-cell and imaging studies point to a non-mnemonic role of the prefrontal cortex, including attentional control of sensory processing, integration of information from different domains, stimulus selection and monitoring of information held in memory. Our own data argue against a modulatory view of the prefrontal cortex and suggest that processes supporting working memory are distributed along ventral and dorsal lateral prefrontal cortex.     

An auditory domain in primate prefrontal cortex.

Although neuroimaging studies confirm the frontal lobe's involvement in language processes and auditory working memory, the cellular and network basis of these functions is unclear. Physiological studies of the frontal lobe in non-human primates have focused on visual working memory and auditory spatial processing in dorsolateral prefrontal cortex (PFC), although the candidate PFC areas for non-spatial acoustic processing lie in the ventrolateral PFC (areas 12 and 45), which receives afferents from physiologically and anatomically defined auditory cortex. We recorded neuronal responses from ventrolateral PFC to auditory cues in awake monkeys under controlled conditions and report that the macaque ventrolateral PFC contains an auditory responsive domain in which neurons show responses to complex sounds, including animal and human vocalizations.     

Working Memory Performance in Typically Developing Children and Adolescents: Behavioral Evidence of Protracted Frontal Lobe Development

Post-mortem histological and in vivo neuroimaging findings both reveal frontal lobe development that extends beyond the adolescent years. Few studies have examined whether this protracted neurodevelopment coincides with improvements in adolescent performance on putative frontal lobe tasks. An instrumental function supported by the frontal lobes is working memory, the ability to maintain and manipulate information “online.” This study investigated the performance of typically developing children and adolescents on a battery of working memory tasks. Findings revealed an improvement in performance on most working memory tasks across the adolescent years. In contrast, no improvement was observed on tasks largely supported by more posterior neural substrates. Current findings indicate a similar unfolding of the executive aspects of verbal working memory as previously demonstrated with spatial working memory. Factor analysis revealed a grouping of working memory tasks based largely on task demands, irrespective of working memory domain, adding support for process-specific models of prefrontal organization. Important implications for typical and atypical frontal lobe development are discussed.     

Prefrontal and parietal contributions to spatial working memory

Functional neuroimaging studies consistently implicate a widespread network of human cortical brain areas that together support spatial working memory. This review summarizes our recent functional magnetic resonance imaging studies of humans performing delayed-saccades. These studies have isolated persistent activity in dorsal prefrontal regions, like the frontal eye fields, and the posterior parietal cortex during the maintenance of positional information. We aim to gain insight into the type of information coded by this activity. By manipulating the sensory and motor demands of the working memory task, we have been able to modulate the frontal eye fields and posterior parietal cortex delay-period activity. These findings are discussed in the context of other neurophysiological and lesion-based data and some hypotheses regarding the differential contributions of frontal and parietal areas to spatial working memory are offered. Namely, retrospective sensory coding of space may be more prominent in the posterior parietal cortex, while prospective motor coding of space may be more prominent in the frontal eye fields.     

Neuronal mechanisms of executive control by the prefrontal cortex

Executive function is considered to be a product of the coordinated operation of various processes to accomplish a particular goal in a flexible manner. The mechanism or system responsible for the coordinated operation of various processes is called executive control. Impairments caused by damage to the prefrontal cortex are often called dysexecutive syndromes. Therefore, the prefrontal cortex is considered to play a significant role in executive control. Prefrontal participation to executive control can be partly explained by working memory that includes mechanisms for temporary active storage of information and processing stored information. For the prefrontal cortex to exert executive control, neuronal mechanisms for temporary storage of information and dynamic and flexible interactions among them are necessary. In this article, we present the presence of dynamic and flexible changes in the strength of functional interaction and extensive functional interactions among temporal information-storage processes in the prefrontal cortex. In addition, recent imaging studies show dynamic changes in functional connectivity between the prefrontal cortex and other cortical and subcortical structures depending upon the characteristics or the temporal context of the task. These observations indicate that the examination of dynamic and flexible modulation in neuronal interaction among prefrontal neurons as well as between the prefrontal cortex and other cortical and subcortical areas is important for explaining how the prefrontal cortex exerts executive control.     

Differential changes in glutamate concentration in the primate prefrontal cortex during spatial delayed alternation and sensory-guided tasks

Glutamate is a major neurotransmitter in the mammalian brain and glutamatergic neurotransmission in the frontal cortex is indicated to play important roles in cognitive operations. We previously examined changes in extracellular dopamine in the primate frontal cortex in cognitive tasks, and in this paper we extend this to glutamate. We employed, as cognitive tasks, a delayed alternation task where the animal must retain information in working memory, and a sensory-guided task in which there is no working memory requirement but there may be more sensory processing requirements. Using the in vivo microdialysis method, we examined changes in extracellular glutamate concentration in the dorsolateral, arcuate, orbitofrontal, and premotor areas of the primate frontal cortex. Compared to basal rest levels, we observed significant increases in glutamate concentration in dorsolateral and arcuate areas of the prefrontal cortex during the sensory-guided task, but did not find significant changes in any of the frontal areas examined during the delayed alternation task. When glutamate concentration was compared between the delayed alternation and sensory-guided tasks, difference was observed only in the dorsolateral prefrontal cortex, especially in the ventral lip area of the principal sulcus. The results indicate the importance of glutamate in processing sensory information but not in retaining information in working memory in the primate dorsolateral and arcuate prefrontal cortex. We also compared the concentration of glutamate and dopamine in the tasks. We found a double dissociation in the concentration of glutamate and dopamine in the dorsolateral area: there was an increase in glutamate but no change in dopamine during the sensory-guided task, whereas there was an increase in dopamine but no change in glutamate during the delayed alternation task. It is thus suggested that in the primate dorsolateral prefrontal cortex, increased glutamate tone without dopamine increase facilitates sensory-guided task performance, while increased dopamine tone without glutamate increase is beneficial for working memory task performance.     

Development of large-scale functional networks over the lifespan

The development of large-scale functional organization of the human brain across the lifespan is not well understood. Here we used magnetoencephalographic recordings of 53 adults (ages 18-89) to characterize functional brain networks in the resting state. Slow frequencies engage larger networks than higher frequencies and show different development over the lifespan. Networks in the delta (2-4 Hz) frequency range decrease, while networks in the beta/gamma frequency range (> 16 Hz) increase in size with advancing age. Results show that the right frontal lobe and the temporal areas in both hemispheres are important relay stations in the expanding high-frequency networks. Neuropsychological tests confirmed the tendency of cognitive decline with older age. The decrease in visual memory and visuoconstructive functions was strongly associated with the age-dependent enhancement of functional connectivity in both temporal lobes. Using functional network analysis this study elucidates important neuronal principles underlying age-related cognitive decline paving mental deterioration in senescence.