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Task instructions influence the cognitive strategies involved in line bisection judgements: evidence from modulated neural mechanisms revealed by fMRI.

Manual line bisection and a perceptual variant thereof (the Landmark test) are widely used to assess visuospatial neglect in neurological patients, but little is known about the cognitive strategies involved. In the Landmark test, one could explicitly compare the lengths of the left and right line segments; alternatively, one could compute the centre of mass of the display. We here investigate with functional MRI if these cognitive strategies modulate the neural mechanisms underlying judgements whether pre-transected horizontal lines are correctly bisected (the Landmark test) in normal volunteers. Functional neuroimaging (fMRI) was carried out in 12 healthy volunteers who judged: (a) whether the line segments on either side of the transection mark were of equal length, and (b) whether the transection mark was in the centre of the line. Line centre judgements were made significantly faster than line length comparisons. Increased neural activity common to both strategies was observed in inferior parietal lobes bilaterally and right temporooccipital cortex. Further activations, most likely reflecting general task demands like response selection and motor control, were found in the precentral gyrus bilaterally, supplementary motor area bilaterally, right anterior cingulate, right dorsolateral prefrontal cortex, cerebellar vermis, and right thalamus and right putamen. Explicit length comparisons (relative to line centre judgements) differentially activated left superior posterior parietal cortex, with a tendency toward activation of the equivalent area on the right, while the reverse comparison revealed differential activation in the lingual gyrus bilaterally and anterior cingulate cortex. The activations observed in inferior parietal cortex during task performance using either strategy are consistent with the results of lesion studies. The differential activation of superior posterior parietal cortex following length instructions suggests that explicit comparisons of spatial extent were implicated. The differential activation of bilateral occipital cortex following centre judgements suggests that the centre of a line is extracted at an early stage of visual processing.

Adult↗

Frontal and parietal networks for conditional motor learning: a positron emission tomography study.

Studies on nonhuman primates show that the premotor (PM) and prefrontal (PF) areas are necessary for the arbitrary mapping of a set of stimuli onto a set of responses. However, positron emission tomography (PET) measurements of regional cerebral blood flow (rCBF) in human subjects have failed to reveal the predicted rCBF changes during such behavior. We therefore studied rCBF while subjects learned two arbitrary mapping tasks. In the conditional motor task, visual stimuli instructed which of four directions to move a joystick (with the right, dominant hand). In the evaluation task, subjects moved the joystick in a predetermined direction to report whether an arrow pointed in the direction associated with a given stimulus. For both tasks there were three rules: for the nonspatial rule, the pattern within each stimulus determined the correct direction; for the spatial rule, the location of the stimulus did so; and for the fixed-response rule, movement direction was constant regardless of the pattern or its location. For the nonspatial rule, performance of the evaluation task led to a learning-related increase in rCBF in a caudal and ventral part of the premotor cortex (PMvc, area 6), bilaterally, as well as in the putamen and a cingulate motor area (CM, area 24) of the left hemisphere. Decreases in rCBF were observed in several areas: the left ventro-orbital prefrontal cortex (PFv, area 47/12), the left lateral cerebellar hemisphere, and, in the right hemisphere, a dorsal and rostral aspect of PM (PMdr, area 6), dorsal PF (PFd, area 9), and the posterior parietal cortex (area 39/40). During performance of the conditional motor task, there was only a decrease in the parietal area. For the spatial rule, no rCBF change reached significance for the evaluation task, but in the conditional motor task, a ventral and rostral premotor region (PMvr, area 6), the dorsolateral prefrontal cortex (PFdl, area 46), and the posterior parietal cortex (area 39/40) showed decreasing rCBF during learning, all in the right hemisphere. These data confirm the predicted rCBF changes in premotor and prefrontal areas during arbitrary mapping tasks and suggest that a broad frontoparietal network may show decreased synaptic activity as arbitrary rules become more familiar.

Adult↗

Parahippocampal reactivation signal at retrieval after interruption of rehearsal.

Verbal information is maintained on-line within working memory by rehearsal. However, we still can recall the verbal information when rehearsal is interrupted. Here we show that this is achieved by reactivation of maintained information. We used event-related functional magnetic resonance imaging to identify brain activation at encoding, during memory delay, and at retrieval, within the same trial of a verbal working memory task. On half of the trials, retrieval was tested after arithmetic distraction to interrupt rehearsal of the remembered verbal items. We found that the parahippocampal cortex (PHC) was highly active at retrieval on trials with distraction compared with trials without distraction. The PHC did not show sustained activation during the memory delay. By contrast, the dorsolateral prefrontal cortex (DLPF), left superior temporal region (ST), and Broca's area showed sustained activation during the memory delay, suggesting their role in maintenance of verbal items. After arithmetic distraction, the DLPF and ST were engaged in arithmetic processing. Thus, these areas could not maintain the verbal items during the distraction. At retrieval of verbal items after the distraction, the DLPF, ST and Broca's area were also active. The activity was taken to reflect reactivated representation of the verbal items. The primary role of the PHC in retrieval may be to trigger the reactivation of these cortical areas that had maintained the remembered items, thereby reactivating the information that is no longer maintained on-line.

Adult↗

Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory.

Previous studies have claimed that weak transcranial direct current stimulation (tDCS) induces persisting excitability changes in the human motor cortex that can be more pronounced than cortical modulation induced by transcranial magnetic stimulation, but there are no studies that have evaluated the effects of tDCS on working memory. Our aim was to determine whether anodal transcranial direct current stimulation, which enhances brain cortical excitability and activity, would modify performance in a sequential-letter working memory task when administered to the dorsolateral prefrontal cortex (DLPFC). Fifteen subjects underwent a three-back working memory task based on letters. This task was performed during sham and anodal stimulation applied over the left DLPFC. Moreover seven of these subjects performed the same task, but with inverse polarity (cathodal stimulation of the left DLPFC) and anodal stimulation of the primary motor cortex (M1). Our results indicate that only anodal stimulation of the left prefrontal cortex, but not cathodal stimulation of left DLPFC or anodal stimulation of M1, increases the accuracy of the task performance when compared to sham stimulation of the same area. This accuracy enhancement during active stimulation cannot be accounted for by slowed responses, as response times were not changed by stimulation. Our results indicate that left prefrontal anodal stimulation leads to an enhancement of working memory performance. Furthermore, this effect depends on the stimulation polarity and is specific to the site of stimulation. This result may be helpful to develop future interventions aiming at clinical benefits.

Adult↗

Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics.

BACKGROUND: Up-regulation of gamma-aminobutyric acidA (GABAA) receptors and decreased GABA uptake in the cerebral cortex of schizophrenics suggest altered GABAergic transmission, which could be caused by primary disturbance of GABA synapses or by decreased production of the transmitter. Decreased production could be due to a shutdown in GABA production or to loss of GABA neurons caused by cell death or their failure to migrate to the cortex during brain development. METHODS: To discriminate between these possibilities, we quantified levels of messenger RNA (mRNA) for the 67-kd isoform of glutamic acid decarboxylase (GAD), the key enzyme in GABA synthesis, and the number and laminar distribution of GAD mRNA--expressing neurons in the dorsolateral prefrontal cortex (DLPFC) of schizophrenics and matched controls, using in situ hybridization-histochemistry, densitometry, and cell-counting methods. These data were compared with the total number of neurons, the number of small, round or ovoid neurons 8 to 15 microns in diameter, and overall frontal lobe volume. As a control, mRNA levels for type II calcium-calmodulin-dependent protein kinase (CamIIK) were quantified. RESULTS: Schizophrenics showed a pronounced decrease in GAD mRNA levels in neurons of layer I (40%) and layer II (48%) and an overall 30% decrease in layers III to VI. There were also strong overall reductions in GAD mRNA levels. The CamIIK mRNA levels showed no significant differences between samples. No differences were found in the total number of neurons nor in small, round or ovoid neurons, which should include a majority of the GABA cells. Prefrontal gray and white matter volume did not differ significantly between controls and schizophrenics. CONCLUSIONS: The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss. This may be brought about by an activity-dependent down-regulation associated with the functional hypoactivity of the DLPFC. The lack of significant alterations in cell numbers in the DLPFC and frontal lobe volume in schizophrenics also implies that overall cortical neuronal migration had not been compromised in development. Previous reports of altered neuronal distribution in the subcortical white matter of schizophrenic brains in comparison with that of controls may indicate disturbances of migration or programmed cell death in the cortical subplate, leading to altered connection formation in the overlying cortex of schizophrenics and activity-dependent down-regulation of neurotransmitter-related gene expression.

Adult↗

Local infusion of an alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys.

BACKGROUND: Stimulation of alpha-2 adrenoceptors in the monkey or rat prefrontal cortex (PFC) has been known to improve spatial working memory (SWM) and stimulation of alpha-1 adrenoceptors in the rat PFC has been reported to impair SWM. The present study attempted to replicate in monkey the rat experiments on alpha-1 adrenoceptor stimulation. METHODS: The alpha-1 adrenergic agonist phenylephrine or the alpha-2 adrenergic agonist guanfacine was infused into the dorsolateral prefrontal cortex (dlPFC) of monkeys performing the delayed-response (DR) task, a task of SWM, to see how the drugs affect SWM performance. RESULTS: Phenylephrine infusion in dlPFC significantly impaired DR performance, whereas guanfacine improved performance. The effects of both drugs were delay-dependent. Infusions outside dlPFC were ineffective. CONCLUSIONS: Stimulation of prefrontal cortical alpha-1 adrenoceptors impairs SWM function in monkeys, consistent with the parallel study in rats, whereas stimulation of alpha-2 adrenoceptors improves SWM, indicating that alpha-1 and alpha-2 adrenoceptors may have opposing roles in the PFC.

Adrenergic alpha-1 Receptor Agonists↗

Neuronal substrates participating in attentional set-shifting of rules for visually guided motor selection: a functional magnetic resonance imaging investigation.

To investigate the neuronal substrates participating in attentional set-shifting for motor selection rules, a functional magnetic resonance imaging study was performed during hand-shape selection tasks. During the session, six right-handed subjects were required to make one of three hand-shapes using their right hands, in response to the hand-shape images on a video screen, following one of the three predefined rules of win, lose, and tie. The selection rules were consistently applied in three conditions (win, tie, and lose), and changed alternately in one condition (alternate win-lose). Thus the alternate win-lose condition requires the shift of rules for motor selection. This alternate condition compared with the win, tie, and lose conditions showed activation in the left middle frontal gyrus, the bilateral inferior frontal gyri, and the left posterior fusiform and lingual gyri. These activation patterns in the prefrontal cortex were similar to those observed during the performance of the Wisconsin Card Sorting Test (WCST), which requires a typical set-shifting ability from one perceptual dimension to another (Berman et al., 1995. Neuropsychologia 33, 1027-1046; Nagahama et al., 1996. Brain 119, 1667-1675; Konishi et al., 1998. Nature Neuroscience 1, 80-84.). Our data may indicate that the dorsolateral prefrontal cortex including the middle and inferior frontal gyri are important in attentional set-shifting of both perceptual and non-perceptual characteristics. Another activation in the fusiform and lingual gyri may have reflected the increased attentional demand for visual processing in the light of a current rule for motor selection.

Adult↗

Lamina-specific abnormalities of AMPA receptor trafficking and signaling molecule transcripts in the prefrontal cortex in schizophrenia.

Ampakines, positive AMPA receptor modulators, can improve cognitive function in schizophrenia, and enhancement of AMPA receptor-mediated currents by them potentiates the activity of antipsychotics. In vitro studies have revealed that trafficking of AMPA receptors is mediated by specific interactions of a complex network of proteins that also target and anchor them at the postsynaptic density (PSD). The aim of this study was to determine whether there are abnormalities of the molecules associated with trafficking and localization of AMPA receptors at the PSD in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. We analyzed AMPA receptor expression in DLPFC in schizophrenia, major depression, bipolar disorder, and a control group, by examining transcript levels of all four AMPA receptor subunits by in situ hybridization. We found decreased GluR2 subunit expression in all three illnesses, decreased GluR3 in major depression, and decreased GluR4 in schizophrenia. However, autoradiography experiments showed no changes in AMPA receptor binding; thus, we hypothesized that these changes in receptor subunit stoichiometry do not alter binding to the assembled receptor, but rather intracellular processing. In situ hybridization for AMPA-trafficking molecules showed decreased expression of PICK1 and increased expression of stargazin in DLPFC in schizophrenia, both restricted to large cells of cortical layer III. These data suggest that AMPA-mediated glutamatergic neurotransmission is compromised in schizophrenia, particularly at the level of AMPA-related PSD proteins that mediate AMPA receptor trafficking, synaptic surface expression, and intracellular signaling.

Adult↗

Physiological activation of a cortical network during performance of the Wisconsin Card Sorting Test: a positron emission tomography study.

To determine the neural circuitry engaged by performance of the Wisconsin Card Sorting Test (WCST), a neuropsychological test traditionally considered to be sensitive to prefrontal lesions, regional cerebral blood flow was measured with oxygen-15 water and positron emission tomography (PET) while young normal subjects performed the test as well as while they performed a specially designed sensorimotor control task. To consider which of the various cognitive operations and other experiential phenomena involved in the WCST PET scan are critical for the pattern of physiological activation and to focus on the working memory component of the test, repeat WCST scans were also performed on nine of the subjects after instruction on the test and practice to criteria. We confirmed that performance of the WCST engages the frontal cortex and also produces activation of a complex network of regions consistently including the inferior parietal lobule but also involving the visual association and inferior temporal cortices as well as portions of the cerebellum. The WCST activation in the dorsolateral prefrontal cortex (DLPFC) remained significant even after training and practice on the test, suggesting that working memory may be largely responsible for the physiological response in DLPFC during the WCST and, conversely, that the DLPFC plays a major role in modulating working memory.

Adolescent↗

Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys.

The terminal distribution of thalamic afferents in primate prefrontal cortex has never been examined in any detail. In the present study, WGA-HRP was injected into major subdivisions of the mediodorsal nucleus (MD) in the rhesus monkey in order to determine 1) The areal distribution of MD projections, 2) the layer(s) in which MD afferents terminate, 3) the tangential pattern of the MD axonal terminals, 4) the cells of origin of the reciprocal corticothalamic pathway, and 5) the degree of reciprocity between the corticothalamic and thalamocortical pathways in the different regions of the prefrontal cortex. As expected on the basis of retrograde degeneration and transport studies, injections centered in the magnocellular (MDmc) subnucleus of MD labeled cells and terminals in the ventral and medial prefrontal cortex. Injections involving ventral MDmc labeled the more lateral of these areas (Walker's areas 11 and 12); injections of the dorsal MDmc labeled the ventromedial regions (areas 13 and 14). In contrast, injections involving mainly the lateral, parvicellular (MDpc) moiety labeled cells and terminals in dorsolateral and dorsomedial areas (Walker's 46, 9, and 8B). Area 8A was labeled most prominently when injections included the multiform portion of MD (MDmf) and area 10 had connections with anterior portions of MD. A dorsal-ventral topography for MDpc exists with dorsal MDpc labeling dorsal and dorsomedial prefrontal areas and ventral MDpc labeling dorsolateral prefrontal cortex. Our findings with respect to MD are consistent with a nucleus-to-field organization of its thalamocortical projection system. Outside of the traditional boundaries of prefrontal cortex, lateral MD projections extended to the supplementary motor area (SMA) and the dorsal part of the anterior cingulate (AC) whereas the medial MD projection targeted the ventromedial cingulate cortex and spared SMA. In addition, a few labeled cells and sparse terminals were found in the inferior parietal lobule, the superior temporal sulcus, and the anterior part of the insula after injections that involved the medial part of MD. Labeled terminals were invariably confined to layer IV and adjacent deep layer III. No terminal label was ever observed in layers I, II, superficial III, V, or VI in any part of the cerebral cortex following injections confined to any part of MD.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗

The effects of a sedative antihistamine, d-chlorpheniramine, on visuomotor spatial discrimination and regional brain activity as measured by positron emission tomography (PET).

Although most people taking antihistamines have experienced sedation and impaired performance, the neural correlates of these sedative properties are not well understood in man. Brain imaging can be used to demonstrate how regional brain activities are altered during such sedative effects. The aim of this study was to visualize the brain mechanism of impaired visuomotor spatial cognition with orally administered d-chlorpheniramine, a first-generation sedative antihistamine, using H(2) (15)O and positron emission tomography (PET). Normal subjects were randomly assigned to two groups (chlorpheniramine and placebo) and performed a spatial discrimination task after the oral administration of 6 mg d-chlorpheniramine or a placebo. The administration of d-chlorpheniramine impaired visuomotor spatial discrimination and altered cortical and subcortical activity. Decreased and increased activities were observed in the right parietal cortex (BA 40) which is related to visuomotor spatial cognition and the posterior cingulate cortex which constitutes the attention system of the brain, respectively. In particular, the brain activities of BA 40 were negatively and positively correlated to those of bilateral caudate nuclei and the dorsolateral prefrontal cortex, respectively. These findings clearly suggest that the alteration in the cortical and subcortical activity contributes to impaired spatial cognition caused by treatment with d-chlorpheniramine.

Adult↗

Effect of catechol-O-methyltransferase val158met genotype on attentional control.

The cingulate cortex is richly innervated by dopaminergic projections and plays a critical role in attentional control (AC). Evidence indicates that dopamine enhances the neurophysiological signal-to-noise ratio and that dopaminergic tone in the frontal cortex is critically dependent on catechol-O-methyltransferase (COMT). A functional polymorphism (val158met) in the COMT gene accounts for some of the individual variability in executive function mediated by the dorsolateral prefrontal cortex. We explored the effect of this genetic polymorphism on cingulate engagement during a novel AC task. We found that the COMT val158met polymorphism also affects the function of the cingulate during AC. Individuals homozygous for the high-activity valine ("val") allele show greater activity and poorer performance than val/methionine ("met") heterozygotes, who in turn show greater activity and poorer performance than individuals homozygous for the low-activity met allele, and these effects are most evident at the highest demand for AC. These results indicate that met allele load and presumably enhanced dopaminergic tone improve the "efficiency" of local circuit processing within the cingulate cortex and thereby its function during AC.

Adult↗

Neural coding of tactile decisions in the human prefrontal cortex.

The neural processes underlying tactile decisions in the human brain remain elusive. We addressed this question in a functional magnetic resonance imaging study using a somatosensory discrimination task, requiring participants to compare the frequency of two successive tactile stimuli. Tactile stimuli per se engaged somatosensory, parietal, and frontal cortical regions. Using a statistical model that accounted for the relative difference in frequencies (i.e., Weber fraction) and discrimination accuracy (i.e., correct or incorrect), we show that trial-by-trial relative frequency difference is represented linearly by activity changes in the left dorsolateral prefrontal cortex (DLPFC), the dorsal anterior cingulate cortex, and bilateral anterior insular cortices. However, a circumscribed region within the left DLPFC showed a different response pattern expressed as activity changes that were monotonically related to relative stimulation difference only for correct but not for incorrect trials. Our findings suggest that activity in the left DLPFC encodes stimulus representations that underlie veridical tactile decisions in humans.

Adult↗

Differential activation in parahippocampal and prefrontal cortex during word and face encoding tasks.

Episodic encoding is the first step in the formation of a memory trace. The relation between type of stimulus material and regional brain activation is not fully understood. We measured brain activation using fMRI in 12 healthy subjects during two experiments, word and face encoding. A widespread network of common activations in both tasks was present in the bilateral frontal (BA44/45), occipital (BA17/18/19) and fusiform gyri (BA37) as well as the right hippocampal formation (BA30). A region-of-interest-analysis for the hippocampal formation and dorsolateral prefrontal cortex (DLPFC) was performed additionally. During face encoding the right dorsal and during word encoding the bilateral ventral hippocampal region was activated. In the prefrontal cortex a lateralization to the left side was present only for word encoding. During encoding, activation in the inferior frontal and hippocampal cortex is modulated by the type of stimulus material.

Adult↗

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↗

Neuroimaging a single thought: dorsolateral PFC activity associated with refreshing just-activated information.

Neuroimaging studies of human working memory (WM) show conflicting results regarding whether dorsolateral prefrontal cortex (PFC) contributes to maintaining information in consciousness or is recruited primarily when information must be manipulated. Using functional magnetic resonance imaging (fMRI), we looked at a minimal maintenance process--thinking back to a single, just-seen stimulus (refreshing). We found greater activity in left dorsolateral PFC (BA9) when participants refreshed a word compared to reading a word once or a second time. Furthermore, recognition memory was subsequently more accurate and faster for items that had been refreshed, demonstrating that a single thought that maintains activation can have consequences for long-term memory. Our fMRI results call into question any class of models of the functional organization of PFC and WM that associates simple and/or maintenance processes only with ventrolateral PFC or that associates dorsolateral PFC only with more complex processes such as manipulation.

Adult↗

Diminishing reciprocal fairness by disrupting the right prefrontal cortex.

Humans restrain self-interest with moral and social values. They are the only species known to exhibit reciprocal fairness, which implies the punishment of other individuals' unfair behaviors, even if it hurts the punisher's economic self-interest. Reciprocal fairness has been demonstrated in the Ultimatum Game, where players often reject their bargaining partner's unfair offers. Despite progress in recent years, however, little is known about how the human brain limits the impact of selfish motives and implements fair behavior. Here we show that disruption of the right, but not the left, dorsolateral prefrontal cortex (DLPFC) by low-frequency repetitive transcranial magnetic stimulation substantially reduces subjects' willingness to reject their partners' intentionally unfair offers, which suggests that subjects are less able to resist the economic temptation to accept these offers. Importantly, however, subjects still judge such offers as very unfair, which indicates that the right DLPFC plays a key role in the implementation of fairness-related behaviors.

Adult↗

Residual differences in language processing in compensated dyslexics revealed in simple word reading tasks.

Using regional cerebral blood flow as an index of cerebral activity we studied dyslexic and control subjects during simple word reading tasks. The groups were pre-tested for reading skill and the dyslexic group had a lower reading performance but could read and comprehend standard texts. The aim was to elucidate differences in the cerebral activation pattern during reading. The tasks were simple enough that performance differences between the groups could be excluded. We found specific differences between the two groups that were dependent on the language task. When the visual route for language information was used, minor qualitative differences were found between the groups pertaining to the dominant hemisphere. Increasing the complexity of the task by using pseudowords activated the left frontal region more in the dyslexic group than in the control group. A similar effect was seen in a minor region in extrastriate lateral occipital cortex (BA 19). This finding indicates that the dyslexics used areas in these regions that the controls did not. On the other hand, the dyslexics activated less in the right angular gyrus, right dorsolateral prefrontal cortex, and in the right pallidum. Reading skill correlated with the level of activity in the right frontal cortex. We conclude, that cerebral activation pattern elicited by reading is different in dyslexics compared to controls in spite of an almost complete functional compensation.

Adult↗