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Functions of the prefrontal cortex in the human brain.

The prefrontal cortex of the human brain is affected by various pathological conditions, and for the apparent theoretical gains and clinical benefits, brain scientists and clinicians alike have for decades endeavored to understand the precise role of this region of the brain. Recent findings in electrophysiological and functional neuroimaging studies provide a better insight into the neuronal activities during various cognitive processes performed by the prefrontal cortex. Nevertheless, some of these findings are at odds with others, and the theorized roles of the prefrontal cortex remain largely under dispute. On the clinical side, a longer history of research provides a wealth of symptom descriptions on the multifaceted prefrontal dysfunction. In the midst of this abundance, however, there still exists a need for coherent categorization of these seemingly disparate symptoms. This task could be done based on the nature of affected cognitive processes and their putative neural substrates. With this view in mind, the present article selectively reviews major anatomical evidence and experimental data together with clinical observations on prefrontal patients in an attempt to integrate findings in science with behavioral data and ultimately to propose a model of functional organization within the prefrontal cortex.

Brain Diseases↗

Dissociating the role of the medial and lateral anterior prefrontal cortex in human planning.

The anterior prefrontal cortex is known to subserve higher cognitive functions such as task management and planning. Less is known, however, about the functional specialization of this cortical region in humans. Using functional MRI, we report a double dissociation: the medial anterior prefrontal cortex, in association with the ventral striatum, was engaged preferentially when subjects executed tasks in sequences that were expected, whereas the polar prefrontal cortex, in association with the dorsolateral striatum, was involved preferentially when subjects performed tasks in sequences that were contingent on unpredictable events. These results parallel the functional segregation previously described between the medial and lateral premotor cortex underlying planned and contingent motor control and extend this division to the anterior prefrontal cortex, when task management and planning are required. Thus, our findings support the assumption that common frontal organizational principles underlie motor and higher executive functions in humans.

Humans↗

Dopaminergic regulation of extracellular gamma-aminobutyric acid levels in the prefrontal cortex of the rat.

Dopaminergic axons in the prefrontal cortex synapse with interneurons as well as pyramidal cells. Electrophysiological data suggest that dopamine depolarizes certain gamma-aminobutyric acid (GABA)-containing interneurons in the cortex. We investigated the dopaminergic regulation of extracellular GABA levels in the prefrontal cortex using in vivo microdialysis. Systemic administration of the mixed D1/D2 dopamine receptor agonist apomorphine increased extracellular GABA levels in the prefrontal cortex, but did not increase levels of glycine; the apomorphine-elicited increase in GABA levels was blocked by tetrodotoxin infusion into the prefrontal cortex. Local administration of the D2 agonist quinpirole into the cortex via the dialysis probe resulted in a dose-dependent increase in extracellular GABA levels. In contrast, administration of the D1 agonist SKF 38393 did not alter GABA levels. The ability of systemic apomorphine to increase extracellular GABA levels in the prefrontal cortex was blocked by local administration of the D2-like antagonist sulpiride to the cortex, but was not attenuated significantly by local perfusion of the D1 antagonist SCH 23390. Similarly, the ability of local infusion of the D2 agonist quinpirole to enhance extracellular GABA levels was blocked by sulpiride but not by SCH 23390. These data suggest that dopamine agonists increase the release of GABA in the prefrontal cortex through a D2-like receptor. In view of posited changes in prefrontal cortical dopamine and GABA systems in schizophrenia, it is possible that changes in GABAergic function in the cortex in schizophrenia are secondary to changes in cortical dopamine function.

Animals↗

Computational perspectives on dopamine function in prefrontal cortex.

Dopamine and the prefrontal cortex are critical for thought and behaviour. Recently, computational models have tried to elucidate the specific and intricate roles of dopamine in the prefrontal cortex, at the neurophysiological, system and behavioral levels, with varying degrees of success.

Animals↗

Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development.

Dysfunction of the prefrontal cortex in schizophrenia may be associated with abnormalities in synaptic structure and/or function and reflected in altered concentrations of proteins in presynaptic terminals and involved in synaptic plasticity (synaptobrevin/ vesicle-associated membrane protein (VAMP), synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin and growth-associated protein-43 (GAP-43)). We examined the immunoreactivity of these synapse-associated proteins via quantitative immunoblotting in the prefrontal cortex of patients with schizophrenia (n=18) and in normal controls (n=23). We also tested the stability of these proteins across successive post-mortem intervals in rat brains (at 0, 3, 12, 24, 48, and 70 h). To investigate whether experimental manipulation of prefrontal cortical development in the rat alters prefrontal synaptic protein levels, we lesioned the ventral hippocampus of rats on postnatal day 7 and measured immunoreactivity of presynaptic proteins in the prefrontal cortex on postnatal day 70. VAMP immunoreactivity was lower in the schizophrenic patients by 22% (P<0.03). There were no differences in the immunoreactivity of any other proteins measured in schizophrenic patients as compared to the matched controls. Proteins were fairly stable up to 24 h and thereafter the abundance of most proteins examined was significantly reduced (falling to as low as 20% of baseline levels at 48-70 h). VAMP immunoreactivity was higher in the lesioned rats as compared to sham controls by 22% (P&<0.03). There were no significant differences between the lesioned rats and sham animals in any other presynaptic protein. These data suggest that apparently profound prefrontal cortical dysfunction in schizophrenia, as well as in an animal model of schizophrenia, may exist without gross changes in the abundance of many synaptic proteins but discrete changes in selected presynaptic molecules may be present.

Adolescent↗

Medullospinal vasomotor neurones mediate hypotension from stimulation of prefrontal cortex.

Electrical stimulation of the prefrontal cortex in anaesthetised, paralysed rats evokes transient hypotension. In this study we have endeavoured to determine whether this evoked response is mediated by the spinal cord-projecting vasomotor neurones of the rostroventrolateral medulla (RVL). The responses of RVL-spinal vasomotor neurones to electrical stimulation of the prefrontal cortex caused a period of inhibition of the neuronal activity in the majority of cases (11 out of 13 neurones tested, 85%) and a short period of excitation in the remaining 2 neurones (15%). The prefrontal cortex-evoked inhibition of RVL-spinal vasomotor neurones was eliminated by iontophoretic application of bicuculline, a GABAa receptor antagonist, to the RVL-spinal vasomotor neurones. Microinjection of 50 nl of bicuculline methiodide into the same area of the RVL where the neurones have been identified converted the prefrontal-evoked hypotension into a vasopressor response. These findings indicate that the hypotension evoked by stimulating the prefrontal cortex is mediated by GABAergic inhibition of the RVL-spinal vasomotor neurones.

Animals↗

Do rats have a prefrontal cortex?

The lack of a single anatomical or functional definition of 'prefrontal cortex' has led to different and, in some respects, controversial views on the existence of a prefrontal cortex in non-primate mammals, in particular in rats. Until the classic paper by Rose and Woolsey [Res. Publ. Assoc. Nerv. Ment. Dis. 27 (1948) 210], the general idea was that a prefrontal cortex is unique to primate species. Rose and Woolsey's 'prefrontal cortex' definition was based upon a single anatomical criterion, i.e. the cortical projection area of the mediodorsal thalamic nucleus. Single criteria, however, do not appear to be sufficient for defining the prefrontal cortex. Therefore, other anatomical and functional characteristics are currently used to identify the prefrontal cortex in different species. Yet, recently the debate about the nature of the prefrontal cortex in non-primate species has been resumed. In the present paper we will compare the structural and functional characteristics of the prefrontal cortex of nonhuman primates and rats. We will argue that rats have a functionally divided prefrontal cortex that includes not only features of the medial and orbital areas in primates, but also some features of the primate dorsolateral prefrontal cortex.

Animals↗

GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls.

The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation. In the present study, which is the first of its type on human cerebral cortex, levels of mRNAs for six GABAA receptor subunits (alpha 1, alpha 2, alpha 5, beta 1, beta 2, gamma 2) and their laminar expression patterns were analyzed in the prefrontal cortex of schizophrenics and matched controls, using in situ hybridization histochemistry and densitometry. Three types of laminar expression pattern were observed: mRNAs for the alpha 1, beta 2, and gamma 2 subunits, which are the predominant receptor subunits expressed in the mature cortex, were expressed at comparatively high levels by cells of all six cortical layers, but most intensely by cells in lower layer III and layer IV. mRNAs for the alpha 2, alpha 5, and beta 1 subunits were expressed at lower levels; alpha 2 and beta 1 were expressed predominantly by cells in layers II, III, and IV; alpha 5 was expressed predominantly in layers IV, V, and VI. There were no significant changes in overall mRNA levels for any of the receptor subunits in the prefrontal cortex of schizophrenics, and the laminar expression pattern of all six receptor subunit mRNAs did not differ between schizophrenics and controls. Because gene expression for GABAA receptor subunits is not consistently altered in the prefrontal cortex of schizophrenics, the previously reported upregulation of muscimol binding sites and downregulation of benzodiazepine binding sites in the prefrontal and adjacent cingulate cortex of schizophrenics are possibly due to posttranscriptional modifications of mRNAs and their translated polypeptides.

Autoradiography↗

Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex.

Cognitive functions regulated by the prefrontal cortex are sensitive to changes in dopaminergic and serotoninergic transmission. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine influences dopaminergic transmission and induces psychotic symptoms in normal and schizophrenic individuals. This study examined the effect of single and repeated ketamine (25 mg/kg, i.p.) administration on extracellular levels of dopamine, GABA and the serotonin metabolite 5-hydroxyindoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vivo microdialysis in conscious rat. In line with earlier studies, we observed a transient five-fold increase in dopamine release following single ketamine administration in drug naive animals. However, we also observed a two-fold increase in basal dopamine levels and an almost complete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days. Extracellular 5-HIAA levels were increased by ketamine in both drug naive and even more enhanced in ketamine-pre-treated animals but without a change in basal 5-HIAA levels. GABA levels were unaffected by either single or repeated ketamine administration. We demonstrate evidence for a differential effect of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in the medial prefrontal cortex. We provide new evidence for a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopamine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of dopaminergic transmission in the prefrontal cortex and may possibly alter the balance between dopamine and serotonin transmission.

Animals↗

Acetylcholine release is elicited in the visual cortex, but not in the prefrontal cortex, by patterned visual stimulation: a dual in vivo microdialysis study with functional correlates in the rat brain.

By its projections to the primary visual and the prefrontal cortices, the basal forebrain cholinergic system is involved in cognitive processing of sensory stimuli. It has been suggested that visual stimulus-induced cholinergic activation of the visual cortex may exert a permissive role on thalamocortical inputs. However, it is not known if visual stimulation elicits cholinergic activation of high-order brain areas in the absence of attentional need. In the present study, we measured the effects of patterned visual stimulation (horizontal grating) on the release of acetylcholine with dual-probe in vivo microdialysis in the visual and the prefrontal cortices of anesthetized rats. We also used retrograde tracing to determine the anatomical relationships of cholinergic neurons with neurons of the visual system and the prefrontal cortex. Finally, we evaluated a functional correlate of this stimulation, namely c-fos immunolabeling. Patterned visual stimulation elicited significant increases in acetylcholine release in the visual cortex, accompanied by an increased number of c-fos immunoreactive neurons in this brain area. In contrast, in the prefrontal cortex, neither the level of acetylcholine release nor the number of c-fos immunoreactive neurons was significantly changed because of the stimulation. Cholinergic basal forebrain neurons projecting to the visual or the prefrontal cortices were both localized within the horizontal limb of the diagonal band of Broca but were not immunoreactive for c-fos during visual stimulation. No parts of the visual system were found to directly project to these basal forebrain neurons. These results suggest the differential involvement of cholinergic projections in the integration of sensory stimuli, depending on the level of activity of the targeted cortical area.

Acetylcholine↗

Dissociation in prefrontal cortex of affective and attentional shifts.

The prefrontal cortex is implicated in such human characteristics as volition, planning, abstract reasoning and affect. Frontal-lobe damage can cause disinhibition such that the behaviour of a subject is guided by previously acquired responses that are inappropriate to the current situation. Here we demonstrate that disinhibition, or a loss of inhibitory control, can be selective for particular cognitive functions and that different regions of the prefrontal cortex provide inhibitory control in different aspects of cognitive processing. Thus, whereas damage to the lateral prefrontal cortex (Brodmann's area 9) in monkeys causes a loss of inhibitory control in attentional selection, damage to the orbito-frontal cortex in monkeys causes a loss of inhibitory control in 'affective' processing, thereby impairing the ability to alter behaviour in response to fluctuations in the emotional significance of stimuli. These findings not only support the view that the prefrontal cortex has multiple functions, but also provide evidence for the distribution of different cognitive functions within specific regions of prefrontal cortex.

Affect↗

Item and order dissociation in humans with prefrontal cortex damage.

Subjects with bilateral, right or left prefrontal cortex damage and age matched controls were tested for item and order recognition memory for spatial location, word, abstract picture and hand position information. Prefrontal cortex damaged subjects showed, in general, no deficits on item recognition tests relative to controls with the exception of a deficit for hand positions. In contrast, prefrontal cortex damaged groups had severe deficits on all order recognition tests relative to controls. With respect to lateralization, order recognition memory deficits occurred for right, bilateral, but not left prefrontal cortex damaged subjects for spatial location information, but for both right and left prefrontal cortex damaged subjects for words, abstract pictures, and hand position. The data suggest that the prefrontal cortex mediates temporal order information for all modalities tested as well as item recognition memory for egocentric spatial information.

Adult↗

A comparative review of rodent prefrontal cortex and working memory.

The prefrontal cortex is critical to working memory processes. Current theories of prefrontal function are largely based on primate behavioural and electrophysiological data. As molecular genetic techniques advance in mice, so investigations into the rodent prefrontal cortex should expand, such that rodent models of prefrontal function during working memory may be used to study the synaptic and molecular basis of the phenomenon. This review attempts to summarize aspects of published data that pertain to working memory and suggest directions that will allow a coherent comparison of prefrontal function and interaction in monkey, rat and mouse.

Animals↗

The prefrontal cortex shows context-specific changes in effective connectivity to motor or visual cortex during the selection of action or colour.

The role of the prefrontal cortex remains controversial. Neuroimaging studies support modality-specific and process-specific functions related to working memory and attention. Its role may also be defined by changes in its influence over other brain regions including sensory and motor cortex. We used functional magnetic imaging (fMRI) to study the free selection of actions and colours. Control conditions used externally specified actions and colours. The prefrontal cortex was activated during free selection, regardless of modality, in contrast to modality-specific activations outside prefrontal cortex. Structural equation modelling (SEM) of fMRI data was used to test the hypothesis that although the same regions of prefrontal cortex may be active in tasks within different domains, there is task-dependent effective connectivity between prefrontal cortex and non-prefrontal cortex. The SEM included high-order interactions between modality, selection and regional activity. There was greater coupling between prefrontal cortex and motor cortex during free selection and action tasks, and between prefrontal cortex and visual cortex during free selection of colours. The results suggest that the functions of the prefrontal cortex may be defined not only by selection-specific rather than modality-specific processes, but also by changing patterns of effective connectivity from prefrontal cortex to motor and sensory cortices.

Adult↗

Memory fields of neurons in the primate prefrontal cortex.

Many prefrontal (PF) neurons convey information about both an object's identity (what) and its location (where). To explore how they represent conjunctions of what and where, we explored the receptive fields of their mnemonic activity (i.e., their "memory fields") by requiring monkeys to remember both an object and its location at many positions throughout a wide portion of central vision. Many PF neurons conveyed object information and had highly localized memory fields that emphasized the contralateral, but not necessarily foveal, visual field. These results indicate that PF neurons can simultaneously convey precise location and object information and thus may play a role in constructing a unified representation of a visual scene.

Animals↗

Ibotenic acid lesions of the dorsal prefrontal cortex disrupt the expression of behavioral sensitization to cocaine.

The present study determined the effect of bilateral lesions of specific cortical or thalamic nuclei that provide excitatory amino acid afferents to the nucleus accumbens (i.e. the dorsal prefrontal cortex, ventral prefrontal cortex, amygdala, hippocampus and periventricular thalamus) on the expression of cocaine-induced behavioral sensitization. Lesions of these nuclei were made during a three-week withdrawal period following repeated daily injections of cocaine or saline. The results indicate that dorsal prefrontal cortex lesions block the expression of behavioral sensitization to cocaine, while ventral prefrontal cortex, fimbria fornix, amygdala and thalamic lesions have no effect. A subsequent microdialysis experiment was performed in order to evaluate the effect of dorsal prefrontal cortex lesions on glutamate transmission in the nucleus accumbens core of cocaine- and saline-pretreated rats. The systemic injection of cocaine produced a significant increase in extracellular glutamate in the nucleus accumbens core among animals with a sham surgery; this effect was blocked by a bilateral lesion of the dorsal prefrontal cortex. Taken together, these results indicate that the dorsal prefrontal cortex, which provides excitatory amino acid input selectively to the core region of the nucleus accumbens, enhances the expression of behavioral sensitization to cocaine by increasing glutamate transmission in this subnucleus.

Animals↗

Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia.

OBJECTIVE: The dorsolateral prefrontal cortex has been implicated in both working memory and the pathophysiology of schizophrenia. A relationship among dorsolateral prefrontal cortex activity, working memory dysfunction, and symptoms in schizophrenia has not been firmly established, partly because of generalized cognitive impairments in patients and task complexity. Using tasks that parametrically manipulated working memory load, the authors tested three hypotheses: 1) patients with schizophrenia differ in prefrontal activity only when behavioral performance differentiates them from healthy comparison subjects, 2) dorsolateral prefrontal cortex dysfunction is associated with poorer task performance, and 3) dorsolateral prefrontal cortex dysfunction is associated with cognitive disorganization but not negative or positive symptoms. METHOD: Seventeen conventionally medicated patients with schizophrenia and 16 healthy comparison subjects underwent functional magnetic resonance imaging while performing multiple levels of the "n-back" sequential-letter working memory task. RESULTS: Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance. Patients with greater dorsolateral prefrontal cortex dysfunction performed more poorly. Dorsolateral prefrontal cortex dysfunction was selectively associated with disorganization symptoms. CONCLUSIONS: These results are consistent with the hypotheses that working memory dysfunction in patients with schizophrenia is caused by a disturbance of the dorsolateral prefrontal cortex and that this disturbance is selectively associated with cognitive disorganization. Further, the pattern of behavioral performance suggests that dorsolateral prefrontal cortex dysfunction does not reflect a deficit in the maintenance of stimulus representations per se but points to deficits in more associative components of working memory.

Adult↗

Recovering meaning: left prefrontal cortex guides controlled semantic retrieval.

Prefrontal cortex plays a central role in mnemonic control, with left inferior prefrontal cortex (LIPC) mediating control of semantic knowledge. One prominent theory posits that LIPC does not mediate semantic retrieval per se, but rather subserves the selection of task-relevant knowledge from amidst competing knowledge. The present event-related fMRI study provides evidence for an alternative hypothesis: LIPC guides controlled semantic retrieval irrespective of whether retrieval requires selection against competing representations. With selection demands held constant, LIPC activation increased with semantic retrieval demands and with the level of control required during retrieval. LIPC mediates a top-down bias signal that is recruited to the extent that the recovery of meaning demands controlled retrieval. Selection may reflect a specific instantiation of this mechanism.

Adolescent↗