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PubMed1999

The dependence of span and delayed-response performance on prefrontal cortex.

Theoretical and empirical research on the cognitive functions of the prefrontal cortex have established that this region mediates what have been called 'executive' processes that can influence working and long-term memory. Despite the accumulation of such empirical evidence, the dependence of purely mnemonic portions of memory tasks on PFC remains unresolved. To address this issue, we performed an analysis of reports of performance on tests of working memory of patients with lesions of the dorsolateral prefrontal cortex, focusing on published reports in the literature of simple span and delayed-response tasks. We found that none of the eleven studies of forward verbal and spatial span in patients with prefrontal cortical lesions that we reviewed (reflecting the performance of 166 individual patients) demonstrated a statistically significant deficit relative to normal controls. In contrast, our review of the delayed-response literature indicated that there are conditions under which PFC lesions disrupt delayed-response performance. Based on the results of our review of the literature, we present testable hypotheses about the working memory functions of the PFC.

Attention↗

PubMed1998

The role of left prefrontal cortex in language and memory.

This article reviews attempts to characterize the mental operations mediated by left inferior prefrontal cortex, especially the anterior and inferior portion of the gyrus, with the functional neuroimaging techniques of positron emission tomography and functional magnetic resonance imaging. Activations in this region occur during semantic, relative to nonsemantic, tasks for the generation of words to semantic cues or the classification of words or pictures into semantic categories. This activation appears in the right prefrontal cortex of people known to be atypically right-hemisphere dominant for language. In this region, activations are associated with meaningful encoding that leads to superior explicit memory for stimuli and deactivations with implicit semantic memory (repetition priming) for words and pictures. New findings are reported showing that patients with global amnesia show deactivations in the same region associated with repetition priming, that activation in this region reflects selection of a response from among numerous relative to few alternatives, and that activations in a portion of this region are associated specifically with semantic relative to phonological processing. It is hypothesized that activations in left inferior prefrontal cortex reflect a domain-specific semantic working memory capacity that is invoked more for semantic than nonsemantic analyses regardless of stimulus modality, more for initial than for repeated semantic analysis of a word or picture, more when a response must be selected from among many than few legitimate alternatives, and that yields superior later explicit memory for experiences.

Amnesia↗

PubMed2000

The role of afferents to the locus coeruleus in the handling stress-induced increase in the release of noradrenaline in the medial prefrontal cortex: a dual-probe microdialysis study in the rat brain.

This study was aimed to identify the neuronal pathways that mediate the handling stress-induced increase in the release of noradrenaline in the medial prefrontal cortex of the rat brain. For that purpose a microdialysis probe was implanted in the vicinity of the locus coeruleus and a second probe was placed in the ipsilateral medial prefrontal cortex. Receptor specific antagonists acting on the alpha(2)-adrenoceptor (50 microM idazoxan), GABA(A) (50 microM bicuculline), GABA(B) (100 microM (3, 4-Dichlorophenyl)methyl]propyl](diethoxymethyl) phosphonic acid; CGP 52432), acetylcholine (10 microM atropine), corticotropin releasing factor (CRF) (100 microM butyl-ethyl-[2,5-dimethyl-7-(2,4, 6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine; CP-154, 526), NMDA glutamate (300 microM (+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; CPP) and non-NMDA glutamate receptors (500 microM 6,7-dinitroquinoxaline-2, 3-dione; DNQX) were infused into the locus coeruleus by retrograde dialysis, whereas extracellular noradrenaline was recorded in the ipsilateral medial prefrontal cortex. During infusion of the various compounds rats were gently handled for 10 min. Infusion of idazoxan potentiates the handling-induced increase in the release of noradrenaline in the medial prefrontal cortex. The infusions of, atropine, bicuculline, CGP 52432 and DNQX were without effect on the handling response. Infusion of the NMDA receptor antagonist CPP or the non-peptide CRF receptor antagonist CP-154,526 suppressed the stimulation of noradrenaline during stress. It is concluded that alpha(2)-adrenoceptors, NMDA glutamate receptors and CRF receptors modify the handling stress response of locus coeruleus neurones. The data suggest no major role for glutamatergic, GABAergic, or cholinergic afferents to the locus coeruleus in mediating the stress response.

Animals↗

PubMed1996

Postnatal development of amygdaloid projections to the prefrontal cortex in the rat studied with retrograde and anterograde tracers.

The prefrontal cortex (PFC) and the amygdala are involved in a number of common functions, such as emotional and social behavior, stress, visceral functions, ingestive behavior, self-stimulation, and certain aspects of learning and memory. The amygdala massively projects to the PFC and may play a role in the developmental plasticity reported for several of these functions. We have studied the normal postnatal development of the amygdaloid projections to the rat prefrontal cortex by using the retrogradely transported fluorescent dye fast blue and the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L). Shortly after birth some fibers were observed in the frontal pole of the rat brain. These fibers were scattered throughout all prefrontal cortical areas. The majority of the amygdaloid cells contributing to this pattern at that stage of development were located in the anterior and ventral basolateral nuclei, whereas a minority were located in the posterior basolateral nucleus. The transition from a diffuse fiber distribution to a characteristic bilaminar pattern occurred around postnatal day 12 in the lateral and rostral medial PFC. The PHA-L injections confirmed the existence of a topographical organization of the amygdalo-prefrontocortical projections. Our observations suggest that the development of amygdala innervation of the PFC parallels the emergence of PFC cytoarchitectural organization.

Aging↗

PubMed1999

Comparison of effects of haloperidol administration on amphetamine-stimulated dopamine release in the rat medial prefrontal cortex and dorsal striatum.

Research has shown that there are important neurochemical differences between the mesocortical and mesostriatal dopamine systems. The work reported in this paper has sought to compare the regulation of dopamine release in the medial prefrontal cortex and the anterior caudate-putamen. In vivo microdialysis was used to recover dialysate fluid for subsequent assay for dopamine concentrations. The responses to D2 antagonist (haloperidol) administration, which has been shown to increase impulse-dependent dopamine release, were compared. Results demonstrated a diminished effect of systemic haloperidol administration on dopamine efflux in the prefrontal cortex. The responses to systemic administration of a nonimpulse-dependent, transporter-mediated, dopamine releaser (d-amphetamine) were also contrasted. Results again demonstrated a diminished pharmacological effect in the cortex. The potential interaction of stimulation of these two types of dopamine release was examined by coadministration of these compounds. Haloperidol pretreatment dramatically potentiated the dopamine-releasing effect of amphetamine administration. This effect was observed in both the cortex and the striatum. Subsequent work demonstrated that this effect of haloperidol was mediated by D2-like receptors in the prefrontal cortex. These results are discussed in relation to other neurochemical and neuroanatomical studies demonstrating sparse densities of dopamine transporter sites and dopamine D2 receptors in the cortex compared with the striatum. They demonstrate a functional correlate to the recently reported, largely extrasynaptic localization of dopamine transporter sites in the prefrontal cortex. Furthermore, they demonstrate the existence of cortical D2-like autoreceptors that may normally be "silent" under basal conditions.

Animals↗

PubMed2003

The medial prefrontal cortex differentially regulates stress-induced c-fos expression in the forebrain depending on type of stressor.

The medial prefrontal cortex (mPFC) plays an important inhibitory role in the hypothalamic-pituitary-adrenal (HPA) axis response. The involvement of the mPFC appears to depend on the type of stressor, preferentially affecting 'psychogenic' stimuli. In this study, we mapped expression of c-fos mRNA to assess the neural circuitry underlying stressor-specific actions of the mPFC on HPA reactivity. Thus, groups of mPFC-lesioned and sham-operated rats were restrained for 20 min or exposed to ether fumes for 2 min. In both cases, the animals were killed at 40 min from the onset of stress. Interestingly, bilateral lesions of the mPFC significantly enhanced c-fos mRNA expression in the hypothalamic paraventricular nucleus of restrained animals, an effect that was paralleled by potentiation of circulating ACTH concentrations in these animals. On the other hand, lesions of the mPFC did not affect neither PVN c-fos mRNA expression nor plasma ACTH concentrations in animals exposed to ether. Lesions of the mPFC also enhanced c-fos activation in the medial amygdala following restraint, but not following ether exposure. Additional regions whose activity was affected by mPFC lesions or stressor differences included the ventrolateral division of the bed nucleus of the stria terminalis, CA3 hippocampus, piriform cortex, and dorsal endopiriform nucleus. Expression of c-fos mRNA was nearly absent in the central amygdala of all stressed animals, regardless of lesion. Furthermore, prefrontal cortex lesions did not change stress-induction levels of c-fos in the CA1 hippocampus, dentate gyrus, anteromedial division of the bed nucleus of the stria terminalis, lateral septum, and claustrum. Taken together, this study indicates that the medial prefrontal cortex differentially regulates cellular activation of specific stress-related brain regions, thus exerting stressor-dependent inhibition of the HPA axis.

Adrenocorticotropic Hormone↗

PubMed2001

Adenosine preferentially suppresses serotonin2A receptor-enhanced excitatory postsynaptic currents in layer V neurons of the rat medial prefrontal cortex.

Serotonin induces 'spontaneous' (non-electrically evoked) excitatory postsynaptic currents in layer V pyramidal neurons in the prefrontal cortex. This is likely due to a serotonin2A receptor-mediated focal release of glutamate onto apical dendrites. In addition, activation of the serotonin2A receptor selectively enhances late components of electrically evoked excitatory postsynaptic currents. In this study, using in vitro intracellular and whole-cell recording in rat brain slices, we examined the role of adenosine in modulating serotonin2A-enhanced 'spontaneous' and electrically evoked excitatory postsynaptic currents in layer V pyramidal neurons in the medial prefrontal cortex. Adenosine and N6-cyclopentyladenosine, an A1 adenosine agonist, markedly suppressed the serotonin2A-induced ('spontaneous') excitatory postsynaptic currents. However, adenosine had no effect on spontaneous miniature (tetrodotoxin-insensitive) postsynaptic potentials. Adenosine also blocked the late excitatory postsynaptic currents induced by the serotonin2A/2C agonist R(-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride. Surprisingly, in contrast to other regions, adenosine had a relatively small effect on electrically evoked fast excitatory postsynaptic currents. These findings represent a novel demonstration of adenosine's ability to preferentially modulate serotonin2A-mediated synaptic events in the medial prefrontal cortex. As the serotonin2A receptor is closely linked with the effects of atypical antipsychotics and hallucinogens, further understanding of the modulators of this receptor such as adenosine may provide useful therapeutic applications.

Adenosine↗

PubMed2004

Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway.

Phencyclidine (PCP) is a psychotomimetic drug that elicits schizophrenia-like symptoms in healthy persons, and administration of PCP to animals is used as a pharmacological model of schizophrenia. We recently demonstrated that systemic administration of PCP to rats produces long-lasting activation of medial prefrontal cortex (mPFC) neurons with augmentation of locomotor activity, whereas direct application of PCP to mPFC neurons has little effect on their firing activity. These findings suggest that PCP-induced activation of mPFC neurons is elicited mainly via excitatory inputs from regions outside the mPFC. In the present study, we examined effects of local application of PCP to the ventral hippocampus (vHIP) on firing activity of PFC neurons in freely moving rats. PCP locally perfused into the vHIP increased spontaneous discharges of PFC neurons during perfusion with augmentation of locomotor activity. Local application of a more selective NMDA receptor antagonist, MK801, to vHIP neurons under anesthesia increased the spontaneous firing rates of most neurons directly projecting to the mPFC, whereas local application of MK801 to mPFC neurons did not induce excitatory responses in any of those neurons. The present results indicate that tonic excitatory inputs from the vHIP to the PFC may trigger development of behavioral abnormalities.

Animals↗

PubMed1979

Cortical afferents to the prefrontal cortex of the cat: a study with the horseradish peroxidase technique.

Following horseradish peroxidase (HRP) injections into different areas within the prefrontal cortex (PFC) of the cat, labeled neurons were found in the cingulate and insular cortex. These results demonstrate that the cat's prefrontal cortex is reached directly from these cortical regions, and that the observed cortical projections are similar to those detected in the monkey's prefrontal cortex.

Animals↗

PubMed1996

Intrategmental infusion of cocaine decreases dopamine release and enhances norepinephrine release in the medial prefrontal cortex.

We evaluated the effects of local cocaine infusion into the A10 (ventral tegmental area), the cell body of the mesocorticolimbic dopaminergic pathway, on the extracellular concentrations of dopamine and norepinephrine in the medial prefrontal cortex, one of its terminal fields. A 1-ml Hamilton syringe was used to infuse a cocaine solution, either 20 or 200 microM, into the ventral tegmental area of anesthetized rats for 120 min through a microdialysis probe. The pure artificial cerebrospinal fluid (0 microM cocaine) infusion served as a control and a lidocaine (100 microM) infusion was administered to prevent the local anesthetic effect of cocaine. After intrategmental cocaine infusion (either 20 or 200 microM), extracellular dopamine and norepinephrine in the ventral tegmental area both increased significantly to a steady state level (208 +/- 42 and 148 +/- 23% for low dose and 220 +/- 24 and 150 +/- 15% for high dose). Simultaneously, the 200-microM cocaine infusion caused a significant decrease in extracellular dopamine (77 +/- 5%) but an increase in norepinephrine (140 +/- 6%) in the medial prefrontal cortex. The local anesthetic, lidocaine, produced no effects on the dopamine or norepinephrine output (neither in the ventral tegmental area nor in the medial prefrontal cortex). This study not only supports recent findings of an increase in extracellular dopamine and norepinephrine in the ventral tegmental area on intrategmental cocaine infusion, but also demonstrates that cocaine infused locally in the ventral tegmental area can decrease dopamine and increase norepinephrine at a remote terminal area (medial prefrontal cortex). Finally, the introduction rate of cocaine into the ventral tegmental area by retrograde microdialysis was found to be 0.83 ng/min for the low dose and 8.14 ng/min for the high dose.

Anesthetics, Local↗

PubMed1994

Effects of systemically administered ceruletide on the in vivo release and metabolism of dopamine in the medial prefrontal cortex of awake, freely moving rats: an in vivo microdialysis study.

The effects of the cholecystokinin octapeptide-related peptide, ceruletide (CER), on the in vivo release and metabolism of dopamine (DA) in the medial prefrontal cortex were examined in awake, freely moving rats, using in vivo microdialysis. Subcutaneously administered CER (200 micrograms/kg) increased extracellular levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), indicating that extracellular levels of DOPAC and HVA may reflect DA release in the medial prefrontal cortex. Bilateral subdiaphragmatic vagotomy markedly attenuated the CER-induced effect, but did not abolish it completely. CER (10(-7) and 10(-10) M), applied locally via the dialysis tube, had no effect on the extracellular levels of either DOPAC or HVA. The CCK-A receptor antagonist, L-364,718 (3 mg/kg, i.p.), completely prevented CER-induced increases in the extracellular levels of DOPAC and HVA. The CCK-B antagonist, L-365,260 (3 mg/kg, i.p.), however, given 1 h before the CER treatment, slightly attenuated the CER-induced increase in the extracellular levels of DOPAC, but not the CER-induced increase in HVA, 60-180 min after the treatment. These findings indicate that systemically administered CER modulates the in vivo release and metabolism of DA in the medial prefrontal cortex. We suggest that systemically administered CER exerts its action on both vagal afferent nerves and the area postrema via CCK-A receptors, thus enhancing the in vivo release and metabolism of DA in the medial prefrontal cortex.

Administration, Topical↗

PubMed2003

Stress and amphetamine induce Fos expression in medial prefrontal cortex neurons containing glucocorticoid receptors.

Exposure to stress or amphetamine potently activates the immediate early gene, c-fos, within medial prefrontal cortex neurons, but the phenotype of these neurons is not known. Fluorescence immunohistochemistry was used to determine that a large subpopulation of medial prefrontal cortex cells expressing Fos protein after restraint and amphetamine also co-express nuclear glucocorticoid receptors (GRs). These findings suggest exposure to amphetamine activates the same medial prefrontal cortex regions responsible for integration of responses to stress, and suggest the potential for AP1-glucocorticoid cross-talk in these cell populations.

Amphetamine↗

PubMed2001

Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus.

Dopamine is implicated in movement, learning, and motivation, and in illnesses such as Parkinson's disease, schizophrenia, and drug addiction. Little is known about the control of dopamine release in humans, but research in experimental animals suggests that the prefrontal cortex plays an important role in regulating the release of dopamine in subcortical structures. Here we used [(11)C]raclopride and positron emission tomography to measure changes in extracellular dopamine concentration in vivo after repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in healthy human subjects. Repetitive TMS of the left dorsolateral prefrontal cortex caused a reduction in [(11)C]raclopride binding in the left dorsal caudate nucleus compared with rTMS of the left occipital cortex. There were no changes in binding in the putamen, nucleus accumbens, or right caudate. This shows that rTMS of the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus. This finding has implications for the therapeutic and research use of rTMS in neurological and psychiatric disorders.

Adult↗

PubMed1997

"Willed action": a functional MRI study of the human prefrontal cortex during a sensorimotor task.

Functional MRI (fMRI) was used to examine human brain activity within the dorsolateral prefrontal cortex during a sensorimotor task that had been proposed to require selection between several responses, a cognitive concept termed "willed action" in a positron emission tomography (PET) study by Frith et al. [Frith, C. D., Friston, K., Liddle, P. F. & Frackowiak, R. S. J. (1991) Proc. R. Soc. London Ser. B 244, 241-246]. We repeated their sensorimotor task, in which the subject chooses to move either of two fingers after a stimulus, by fMRI experiments in a 2.1-T imaging spectrometer. Echo-planar images were acquired from four coronal slices in the prefrontal cortex from nine healthy subjects. Slices were 5 mm thick, centers separated by 7 mm, with nominal in-plane spatial resolution of 9.6 x 5.0 mm2 for mean data. Our mean results are in agreement with the PET results in that we saw similar bilateral activations. The present results are compared with our previously published fMRI study of a verbal fluency task, which had also been proposed by Frith et al. to elicit a "willed action" response. We find a clear separation of activation foci in the left dorsolateral prefrontal cortex for the sensorimotor (Brodmann area 46) and verbal fluency (Brodmann area 45) tasks. Hence, assigning a particular activated region to "willed action" is not supported by the fMRI data when examined closely because identical regions are not activated with different modalities. Similar modality linked activations can be observed in the original PET study but the greater resolution of the fMRI data makes the modality linkages more definite.

Female↗

PubMed2001

Increased AMPA receptor function in slices containing the prefrontal cortex of spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) are used as a genetic model for attention-deficit hyperactivity disorder (ADHD), since they have behavioral characteristics that mimic the major symptoms of ADHD. We have previously shown that dopaminergic and noradrenergic systems are altered in the prefrontal cortex of SHR compared to normotensive Wistar-Kyoto (WKY) control rats. We also showed that neural circuits that use glutamate as a neurotransmitter increased norepinephrine release from rat prefrontal cortex slices and that glutamate caused significantly greater release of norepinephrine from prefrontal cortex slices of SHR than from those of WKY. The effect of glutamate did not appear to be mediated by NMDA receptors, since NMDA did not exert any effect on norepinephrine release and the NMDA receptor antagonist MK-801 did not reduce the effect of glutamate. In this investigation we show that the stimulatory effect of glutamate is greater in SHR than in WKY and that the effect can be antagonised by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The results suggest that glutamatergic neuron terminals in rat prefrontal cortex establish synaptic contacts with noradrenergic terminals to enhance norepinephrine release by activation of AMPA receptors and that this enhancement is amplified in SHR.

Animals↗

PubMed1988

Organization of cortical and subcortical projections to medial prefrontal cortex in the cat.

We have analyzed the cortical and subcortical afferent connections of the medial prefrontal cortex (MPF) in the cat with the specific aim of characterizing subregional variations of afferent connectivity. Thirteen tracer deposits were placed at restricted loci within a cortical district extending from the proreal to the subgenual gyrus. The distribution throughout the forebrain of retrogradely labeled neurons was then analyzed. Within the thalamus, retrogradely labeled neurons were most numerous in the mediodorsal nucleus and in the ventral complex. The projection from each region exhibited continuous topography such that more medial thalamic neurons were labeled by tracer from more ventral and posterior cortical deposits. Marked retrograde labeling without any sign of topographic order occurred in a narrow medioventral sector of the lateroposterior nucleus. Several additional thalamic nuclei contained small numbers of labeled neurons. In a subset of nuclei closely affiliated with the limbic system (the parataenial, paraventricular, reuniens, and basal ventromedial nuclei), retrograde labeling occurred exclusively after deposits at extremely ventral and posterior cortical sites. Within the amygdala, retrogradely labeled neurons occupied the anterior basomedial nucleus, the posterior basolateral nucleus, and a narrow strip of the lateral nucleus immediately adjoining the basolateral nucleus. The number of labeled neurons was greater after more ventral deposits. Very ventral deposits resulted in extensive labeling of the cortical amygdala. Within the cerebral cortex, the distribution of labeled neurons depended on the location of the tracer deposit. Comparatively dorsal deposits produced prominent retrograde transport to the anterior and posterior cingulate areas, to the agranular insula, and to lateral prefrontal cortex. Comparatively ventral deposits gave rise to prominent labeling of the hippocampal subiculum, various parahippocampal areas, and prepiriform cortex. On the basis of afferent connections, it is possible to divide the cat's medial prefrontal cortex into an infralimbic component, MPFil, marked by strong afferents from prepiriform cortex and the cortical amygdala, and a dorsal component, MPFd, without afferents from these structures. Further, within MPFd, it is possible to define an axis, running from ventral and posterior to dorsal and anterior levels, along which limbic afferents gradually become weaker and projections from cortical association areas gradually become stronger.

Acetylcholinesterase↗

PubMed2000

Neural mechanisms of memory retrieval: role of the prefrontal cortex.

In the primate brain, long-term memory is stored in the neocortical association area which is also engaged in sensory perception. The coded representation of memory is retrieved via interactions of hierarchically different cortical areas along bottom-up and top-down anatomical connections. The functional significance of the fronto-cortical top-down neuronal projections has been relevantly assessed in a new experimental paradigm using posterior-split-brain monkeys. When the splenium of the corpus callosum and the anterior commissure were selectively split, the bottom-up visual signal originating from the unilateral striate cortex could not reach the contralateral visual cortical areas. In this preparation, long-term memory acquired through visual stimulus-stimulus association learning was prevented from transferring across hemispheres. Nonetheless, following the presentation of a visual cue to one hemisphere, the prefrontal cortex could instruct the contralateral hemisphere to retrieve the correct stimulus specified by the cue. These results support the hypothesis that the prefrontal cortex can regulate memory recall in the absence of bottom-up sensory input. In humans, functional neuroimaging studies have revealed activation of a distributed neural network, including the prefrontal cortex, during memory retrieval tasks. Thus, the prefrontal cortex is consistently involved in retrieval of long-term memory in primates.

Animals↗

PubMed2003

Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings.

Working memory (WM) deficits are a persistent, disabling and relatively treatment-resistant feature of schizophrenia that may underlie many cognitive deficits and symptoms. They are associated with prefrontal cortex dysfunction. While most neuroimaging studies of WM demonstrate "task-related hypofrontality" in schizophrenic relative to healthy subjects, several recent studies have reported equal or increased prefrontal activity. These findings challenge central assumptions regarding cognitive deficits and prefrontal cortex dysfunction in schizophrenia. The goal of this review is to reconcile these seemingly discrepant findings. Methodological factors addressed include the use of intersubject averaging, WM task parameters and the reliability of the measures. Factors intrinsic to schizophrenia and their relevance to the selection of experimental methods and the interpretation of group data are also discussed. Both hypo- and hyperfrontality are hypothesized to be valid and informative reflections of prefrontal cortex dysfunction in schizophrenia. Due to the heterogeneity and variability of both performance and regional recruitment in schizophrenia, whether individual data is considered, the level and type of WM demands and the composition of the sample with regard to performance deficits all influence study outcome and contribute to discrepancies. Although the prefrontal cortex is consistently implicated in WM deficits, the basis of its dysfunction and its exact contribution remain unclear. Future work might focus on delineating the exact WM processes, domains and components that are deficient. In addition, variability in behavior and activation might best be regarded as intrinsic to schizophrenia and having a neural basis that requires explanation. In combination with other techniques, neuroimaging can identify the neural circuitry responsible for WM deficits and elucidate the contribution of each anatomical component.

Humans↗