Left Prefrontal Regions Research Articles

Metaphorical vs. literal word meanings: fMRI evidence against a selective role of the right hemisphere

The neural networks associated with processing metaphorical word meanings were investigated in normal adults using fMRI. Subjects listened to sets of three adjectives and decided whether the last two had a similar meaning. One condition required accessing the literal meaning of the middle word (e.g., hot– cold– chilly), whereas the other condition required accessing its nonliteral, or metaphorical, meaning (e.g., hot– cold– unfriendly). Direct comparison of the nonliteral vs. literal condition showed reliable activity only in left prefrontal and temporo-parietal regions. These results argue against a selective role of the right hemisphere (RH) in accessing metaphorical word meanings. In line with a growing literature, these findings suggest that prior reports of greater RH involvement for metaphorical language might reflect the increased complexity of figurative language rather than an RH specialization for understanding metaphors.

FMRI reveals alteration of spatial working memory networks across adolescence

Recent studies have described neuromaturation and cognitive development across the lifespan, yet few neuroimaging studies have investigated task-related alterations in brain activity during adolescence. We used functional magnetic resonance imaging (fMRI) to examine brain response to a spatial working memory (SWM) task in 49 typically developing adolescents (25 females and 24 males; ages 12-17). No gender or age differences were found for task performance during SWM. However, age was positively associated with SWM brain response in left prefrontal and bilateral inferior posterior parietal regions. Age was negatively associated with SWM activation in bilateral superior parietal cortex. Gender was significantly associated with SWM response; females demonstrated diminished anterior cingulate activation and males demonstrated greater response in frontopolar cortex than females. Our findings indicate that the frontal and parietal neural networks involved in spatial working memory change over the adolescent age range and are further influenced by gender. These changes may represent evolving mnemonic strategies subserved by ongoing adolescent brain development.

Neural mechanism in anterior prefrontal cortex for inhibition of prolonged set interference

Once one cognitive set dominates our behavior, it continues to influence subsequent behavior for a while even after a task to be performed is changed to another. Despite abundant knowledge of the inhibitory mechanisms that are recruited at the first trial after the change (the first inhibition trial), little is known about the inhibition of prolonged proactive interference from a previous set that lingers for several trials after the first inhibition trial. The present functional MRI study explored the neural mechanisms for inhibition of a previous set that were recruited after the first inhibition trial. A modified Wisconsin Card Sorting Test was used where "dual-match stimuli" were intermittently presented and allowed subjects to perform correctly based on previously appropriate, now inappropriate, responses. In response to the dual-match stimulus at "release" trials presented after the first inhibition trials, the subjects were transiently exempted from inhibiting the prolonged previous set. As expected from the exempted inhibitory demands, significant reaction time decrease was revealed in the release trials. Consistent with the behavioral results, transient signal decrease time-locked to the release trials was revealed in the left anterior part of the superior frontal sulcus. Moreover, the anterior prefrontal region was not sensitive to the task change, which exhibited a marked contrast to the left posterior inferior prefrontal region that showed significant signal changes in both events. These results revealed multiple inhibitory mechanisms in the lateral prefrontal cortex that are recruited in different temporal contexts of the interference from a previous cognitive set.

Functional disconnectivity in subjects at high genetic risk of schizophrenia

Schizophrenia is a highly heritable psychotic disorder. It has been suggested that deficits of the established state arise from abnormal interactions between brain regions. We sought to examine whether such connectivity abnormalities would be present in subjects at high genetic risk for the disorder. Functional connectivity analysis was carried out on functional MRI images from 21 controls and 69 high risk subjects performing the Hayling sentence completion task; 27 high risk subjects reported isolated psychotic symptoms, the remaining high risk subjects and controls did not. There were no significant differences in task performance between the groups. Based on previous findings we hypothesized: (i) state-related differences in connectivity between dorsolateral prefrontal cortex and lateral temporal lobe; (ii) genetically mediated reductions in a medial prefrontal-thalamic-cerebellar network; and (iii) increased prefrontal-parietal connectivity in high risk subjects (to a greater extent in those with isolated psychotic symptoms). Connectivity analysis was performed in two ways: with and without variance associated with task effects modelled and removed from the data. We did not find evidence to support our first hypothesis with either analysis method. However, consistent with hypothesis (ii), decreased connectivity between right medial prefrontal regions and contralateral cerebellum was found. This was only statistically significant in the analysis with task effects modelled and removed from the data. Finally, consistent with hypothesis (iii), increased connectivity between the left parietal and left prefrontal regions in high risk subjects was found in both analyses. These results, all in a situation uncontaminated by the effects of anti-psychotic medication, performance differences and prolonged illness, suggest there are abnormalities in functional connectivity over and above those attributable to task effects in high risk subjects. These connectivity abnormalities may underlie the diverse deficits seen in the established condition and the more subtle deficits seen in close relatives of those with the disorder.

Resting state glucose utilization and the CERAD cognitive battery in patients with Alzheimer's disease

The present study examined the cortical functional representation of neuropsychological domains in Alzheimer's disease (AD) using positron emission tomography (PET) and the neuropsychological assessment battery of the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Thirty patients with clinical probable AD and 10 elderly healthy controls underwent 18FDG brain PET imaging during a resting state. Correlations between metabolic values and cognitive measures were determined using a region of interest analysis with NEUROSTAT (University of Michigan, USA) and a voxel-based analysis with SPM96 (Wellcome Department, London, UK). Specific correlations were seen between measures of episodic memory, verbal fluency and naming and left hemispheric temporal and prefrontal metabolism. Drawing was correlated with metabolism in left prefrontal and left inferior parietal regions. The presented data support the use of metabolic–cognitive correlations to demonstrate the neuronal substrates of cognitive impairment in AD. Subtests of the CERAD battery give a good representation of left, but not of right hemisphere function in AD.

Cerebral Hemodynamic Changes in Response to an Executive Function Task in Children with Attention-Deficit Hyperactivity Disorder Measured by Near-Infrared Spectroscopy

The aim of the present study was to evaluate the hemodynamic changes in both prefrontal regions induced by a cognitive task in children with a developmental attention-deficit disorder in comparison to normal controls using near-infrared spectroscopy (NIRS). A total of 11 boys with a mean age of 10.4 (+/-1.2) years that met the DSM-IV criteria for attention-deficit hyperactivity disorder (ADHD) participated in the study and were compared with 9 healthy age- and sex-matched controls. Using a trail-making test designed for the task of connecting numbers from 1-90 in four sets, changes in oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin, tissue oxygenation index (TOI), and cerebral blood volume (CBV) were measured by near-infrared spectroscopy. During the first test set, designed as a short-attention task, the children with ADHD showed significant increases in O2Hb and CBV, whereas the controls showed no significant changes. During the 4 task cycles in which extended attention was demanded, both groups showed increases in O2Hb and CBV, but only the controls showed an additional increase in HHb in the left prefrontal region. In the ADHD group only, TOI showed an increase mainly on the left side. NIRS is a sensitive tool for measuring differences in hemodynamic changes between boys with ADHD and normal controls. Overall, the normal controls showed lateralized oxygen consumption in the left prefrontal cortex during an extended-attention task, whereas the boys with ADHD showed an imbalance between oxygenated and deoxygenated hemoglobin during the short- and extended-attention tasks.

Aging affects both perceptual and lexical/semantic components of word stem priming: An event-related fMRI study

In this event-related fMRI study, brain activity patterns were compared in extensive groups of young ( N = 25) and older ( N = 38) adults, while they were performing a word stem completion priming task. Based on behavioral findings, we tested the hypothesis that aging affects only the lexical/semantic, but not the perceptual component of word stem priming. To this end, we distinguished between priming-related activity reductions in posterior regions involved in visual processing, and regions associated with lexical/semantic retrieval processes, i.e., left lateral temporal and left prefrontal regions. Both groups revealed significant priming-related response time reductions. However, in accordance with earlier findings, a larger priming effect was found in the group of young participants. In line with previous imaging studies, the groups showed common priming-related activity reductions in the anterior cingulate, and the left inferior prefrontal cortex extending into the anterior portion of the left superior temporal gyrus, and at lower thresholds also in the right occipital lobe. However, when directly comparing the groups, greater priming-related reductions were found for the young group in the left anterior superior temporal gyrus and the right posterior occipital lobe. These findings suggest that, converse to current psychological views, aging affects both perceptual and lexical/semantic components of repetition priming.

Language-Related Activations in the Left Prefrontal Regions Are Differentially Modulated by Age, Proficiency, and Task Demands

It remains to be elucidated how cortical activations are modulated by factors of age, proficiency, and language task demands when mastering first language (L1) and a second language (L2). Using functional magnetic resonance imaging, we tested subjects aged 13 (the age 13 group) and 19 (the age 19 group), thereby comparing the cortical activations involved in past-tense verb identification with those involved in verb matching. We found that the activation in the dorsal triangular part of the left inferior frontal gyrus (IFG) was lower, corresponding to a higher proficiency in English (L2) in the older subjects, suggesting that the proficiency level plays a major role in the activation of this region during L2 acquisition. Moreover, the lower activation in the triangular and orbital parts of the left IFG (F3t/F3O) for the irregular past tense corresponding to a higher proficiency in L2, together with the nonsignificant activation for the regular past tense when its performance almost reached perfection for age 19, suggests that the modulation of the left F3t/F3O activation reflects language task demands for identifying correct past-tense forms. On the other hand, the left F3t/F3O activation in Japanese (L1) for age 13 was significantly greater than that for age 19, despite the matched performances in L1. These results suggest that the left IFG subserves language-specific functions that are critically required when mastering any language.

What vs. where in touch: an fMRI study

Two streams have been identified in cortical visual processing: a ventral stream for form, color, and features, and a dorsal stream for spatial characteristics and motion. We investigated whether similar “what” and “where” dissociations of function exist for human somatosensory processing. Using identical stimuli and hand movements, subjects either performed tactile object recognition (TOR) and ignored location or performed tactile object localization (LOC) and ignored identity. A matched-movement control task separated activation associated with sensorimotor input from higher-level cognitive contributions. Results confirmed separate processing streams for TOR and LOC. TOR activated the frontal pole as well as bilateral inferior parietal and left prefrontal regions involved in tactile feature integration and naming. LOC activated bilateral superior parietal areas involved in spatial processing. The dissociation of object and spatial processing streams appears to be a modality general organizational principle in the brain.

Dissociation of cortical regions modulated by both working memory load and sleep deprivation and by sleep deprivation alone

Working memory is an important mental capacity that is compromised following sleep deprivation (SD). To understand how working memory load interacts with state to influence brain activation in load-sensitive regions, and the extent to which SD-related changes are common across different loads, we used fMRI to study twelve healthy subjects following 24 h of SD using a verbal n-back task with three load levels. Performance decline was observed by way of reduced accuracy and slower response times following SD. The left prefrontal region and thalamus showed load dependent activity modulation that interacted with state. The right parietal and anterior medial frontal regions showed load dependent changes in activity as well as an effect of state. The anterior cingulate and occipital regions showed activation that displayed state effects that were independent of working memory load. These findings represent a step toward identifying how different brain regions exhibit varying vulnerability to the deleterious effects of SD on working memory.

Gray matter abnormalities in paranoid schizophrenia and their clinical correlations

Numerous imaging studies have shown structural brain abnormalities in schizophrenia. Recently, voxel-based morphometry enabled whole brain analysis beyond the regions of interest (ROI). Regional gray matter concentrations of magnetic resonance (MR) images from 35 patients with paranoid schizophrenia were compared with those from 35 age- and sex-matched controls, and their clinical correlations were explored using voxel-based morphometry. Gray matter concentrations in the patients were significantly reduced in the left insular and dorsolateral prefrontal regions, and bilaterally in the medial frontal, anterior cingulate, inferior frontal and superior temporal regions. On the other hand, gray matter concentrations in the bilateral cerebellum and right striatum were significantly increased in the patients compared with controls. A negative correlation between the score for the severity of ‘lack of insight and judgment’ and gray matter concentrations in the left posterior and right anterior cingulate and bilateral inferior temporal regions including the lateral fusiform gyri was found. These results suggest the important roles of the paralimbic structures in the pathophysiology of schizophrenia and the involvement of the perceptual and monitoring systems in the mechanism of insight.

Neuroanatomical correlates of locative prepositions

Very little research has explored which neural systems may be important for retrieving the meanings of locative prepositions (e.g., in, on, around). To begin to address this knowledge gap, we conducted a lesion study in which we tested the hypothesis that processing the meanings of locative prepositions depends on neural structures in the left inferior prefrontal cortex and left inferior parietal cortex. Seventy‐eight subjects with focal, stable lesions to various parts of the telencephalon and a comparison group of 60 normal participants were studied with tasks that require production, comprehension, and semantic analysis of locative prepositions. In support of our hypothesis, we found that in subjects with impaired knowledge of locative prepositions, the highest region of lesion overlap was in the left frontal operculum and the left supramarginal gyrus, and in the white matter subjacent to these two areas. In a second study, focused on six subjects who had pervasive defects for locative preposition knowledge, we confirmed that such defects were associated specifically with damage to the posterior left frontal operculum, white matter subjacent to this region, and white matter underneath the inferior parietal operculum. These subjects did not have basic impairments in spatial processing or working memory, and they had relatively well‐preserved processing of conceptual knowledge for actions and various categories of concrete entities (e.g., persons, animals, tools). All six subjects, however, had defects in naming actions, and some of them also had defective naming of some categories of concrete entities. Overall, the findings converge nicely with recent results from functional imaging approaches, and with classic studies from the aphasia‐based literature, and suggest that the left inferior prefrontal and left inferior parietal regions have crucial–albeit not exclusive–roles in processing knowledge associated with locative prepositions.

Recognition memory for studied words is determined by cortical activation differences at encoding but not during retrieval

Prior work has shown that when responses to incidentally encoded words are sorted, subsequently remembered words elicit greater left prefrontal BOLD signal change relative to forgotten words. Similarly, low-frequency words elicit greater activation than high-frequency words in the same left prefrontal regions, contributing to their better subsequent memorability. This study examined the relative contribution of encoding and retrieval processes to the correct recognition of target words. A mixture of high- and low-frequency words was incidentally encoded. Scanning was performed at encoding as well as during retrieval. During encoding, greater activation in the left prefrontal and anterior cingulate regions predicted a higher proportion of hits for low-frequency words. However, data acquired during recognition showed that word frequency did not modulate activation in any of the areas tracking successful recognition. This result demonstrates that under some circumstances, the recognition of studied words is determined purely by processes that are active during encoding. In contrast to the finding for hits, activation associated with correctly rejected foils was modulated by word frequency, being higher for high-frequency words in the left lateral parietal and anterior prefrontal regions. These findings were replicated in two further experiments, one in which the number of test items at recognition was doubled and another where encoding strength for high-frequency words was varied (once vs. 10 times). These results indicate that word frequency modulates activity in the left lateral parietal and anterior prefrontal regions contingent on whether the item involved is correctly recognized as a target or a foil. This observation is consistent with a dual process account of episodic memory.

Neural systems for word meaning modulated by semantic ambiguity

One important issue in neuroimaging research on language is how the brain processes and represents lexical semantics. Past studies with various paradigms reveal that the left inferior prefrontal and mid-superior temporal regions play a crucial role in semantic processing. Those studies, however, typically utilize words having a precise and dominant meaning as stimuli and have not manipulated lexico-semantic ambiguity, a key feature of human language, as an experimental variable. Here, we used a word generation paradigm to examine whether neuroanatomical networks for meaning are modulated by lexical ambiguity. We found that, compared with semantically precise words, semantically ambiguous words were mediated by strong brain activations in the left dorsal–lateral frontal areas, the anterior cingulate, and the right inferior parietal lobe. Semantically precise words, instead, were associated with the left inferior prefrontal and mid-superior temporal sites. These findings indicate that semantic analysis of written words is a dynamic process involving coordination of widely distributed neural subsystems, which are weighted by semantic ambiguity.

Drugs and human memory (part 2). Clinical, theoretical, and methodologic issues.

Drugs and human memory (part 2). Clinical, theoretical, and methodologic issues.

Functional-neuroanatomic correlates of recollection: implications for models of recognition memory.

Recognition decisions can be based on familiarity, the sense that an item was encountered previously (item memory), and on recollection, the conscious recovery of contextual information surrounding a previous encounter with the item (e.g., source memory). Recognition with recollection is thought to depend on multiple mechanisms, including prefrontal "control" processes that guide retrieval and recapitulation mechanisms that reactivate posterior neocortical representations that were present at encoding. However, uncertainty remains regarding the precise nature of prefrontal contributions to recollection and the selectivity of recapitulation to veridical recollection. The present event-related functional magnetic resonance imaging study sought to examine whether regions showing "old-new" effects support processes sensitive to recollection success or recollection attempt and whether recapitulation of neocortical representations emerge during veridical recollection as well as during false recognition (i.e., false alarms) or whether false recognition resembles familiarity-based responding. Results revealed that multiple left prefrontal cortical regions were engaged during attempts to recollect previous contextual (source) details, regardless of the nature of the to-be-recollected details and of source recollection outcome (successful vs unsuccessful). Recapitulation effects were observed in regions sensitive to the encoding task, suggesting that veridical recollection entails the reactivation of processes or representations present during encoding. Importantly, in contrast to leading models of recognition memory, false alarms also appeared to be based partially on recollection, as revealed through false recapitulation effects. Implications for neural and cognitive models of recognition are considered.

Differential contribution of left and right prefrontal cortex to associative cued-recall memory: a parametric PET study.

Several brain imaging studies have implicated prefrontal regions bilaterally during cued-recall memory tasks and yet the functional significance of these regions remains poorly understood. Using PET, we examined the neural activity in prefrontal regions of 15 subjects while they performed three cued-recall tasks differing in pre-experimental semantic associations between cues and targets. This manipulation produced varying levels of retrieval performance when one member (a semantic category name) of the triad was used as a cue for the retrieval of the other two members. The percentage of items correctly recalled was 10, 46, and 70 in the low, medium, and high cued-recall conditions, respectively. Linear contrast analyses of the PET data identified brain regions where neural activity varied with the number of items retrieved from memory. A left lateral prefrontal region showed maximal activity during the high cued-recall condition, which likely reflects processes involved in retrieval success and possibly in the generation of memory responses. Three right prefrontal regions (anterior and dorsolateral) showed maximal activity during the low cued-recall condition, which likely reflects processes involved in memory search/monitoring. These findings add further support for a bilateral prefrontal contribution to memory cued-recall tasks and point to differential roles of the two hemispheres.

Prefrontal hemodynamic response to verbal-fluency task and hyperventilation in bipolar disorder measured by multi-channel near-infrared spectroscopy

Background: Many neuroimaging studies of patients with bipolar disorder have demonstrated functional hypofrontality (reduced activation of the frontal cortex), although this finding is still controversial. We previously found hypoactivation of the left prefrontal region in remitted subjects with bipolar disorder measured by one-channel near-infrared spectroscopy (NIRS). The aim of the present study was to clarify whether or not this finding was due to altered cerebral lateralization or caused by reduced cerebrovascular reactivity. Methods: We enrolled nine remitted patients with bipolar disorder and nine normal controls. Hemodynamic responses in the prefrontal cortex during the verbal-fluency and hyperventilation tasks were monitored by 24-channel NIRS, which can measure oxygenated hemoglobin (OxyHb), deoxygenated hemoglobin, and total hemoglobin (TotalHb). Results: The increases of OxyHb and TotalHb in the bipolar group were significantly smaller than that in the controls during the verbal-fluency task. The response of TotalHb during hyperventilation in the bipolar group was weaker than that in the controls. Limitations: The sample size was small. Conclusions: These findings suggest that the bilateral hypofrontality to a cognitive task is seen in remitted subjects with bipolar disorder, which may be related to vascular function as measured by the response to hyperventilation.

FMRI BOLD response to alcohol stimuli in alcohol dependent young women

Background: Cue reactivity in alcohol dependent adults has revealed autonomic, cognitive, and neural responses to alcohol-related stimuli that differ from those of nonabusers. Cue reactivity and craving responses have not been studied in youth. Method: Alcohol-dependent young women ( n=8) and female light social drinkers ( n=9) ages 18–24 were administered an alcohol cue reactivity task during functional magnetic resonance imaging (fMRI) to examine brain response to alcohol-related words. Results: Alcohol dependent young women demonstrated significantly more blood oxygen level dependent (BOLD) response than nonabusers during alcohol word presentation trials relative to neutral word trials in subcallosal, anterior cingulate, left prefrontal, and bilateral insular regions ( P<.025). However, controls showed greater response to alcohol words in some right hemisphere cortical regions. Increased craving after cue exposure correlated with increased subcallosal cortex BOLD response to alcohol cues ( r=.87) among alcohol dependent subjects. Conclusions: This pilot study corroborates previous reports of increased limbic and frontal response to substance cues and extends these findings to young alcohol dependent women. This limbic reaction may underlie the elevated physiological response and altered cognitive reactions to alcohol stimuli that are observed in alcohol dependent individuals.

Cortical neurophysiology of anticipatory anxiety: an investigation utilizing steady state probe topography (SSPT)

The precise role of the cortex in human anxiety is not well characterised. Previous imaging research among healthy controls has reported alterations in regional cerebral blood flow (rCBF) within the prefrontal and temporal cortices during periods of anxious anticipation; however, the temporal dynamics of this activity has yet to be examined in detail. The present study examined cortical Steady State Probe Topography (SSPT) changes associated with anticipatory anxiety (AA), allowing examination of the temporal continuity and the excitatory or inhibitory nature of AA activations. We recorded Steady State Visually Evoked Potentials (SSVEPs) at 64 scalp locations, skin conductance, and self reported anxiety among 26 right-handed males while relaxed and during the anticipation of an electric shock. Relative to the baseline condition, the AA condition was associated with significantly higher levels of self-reported anxiety and increased phasic skin conductance levels. Across the seven second imaging window, AA was associated with increased SSVEP latency within medial anterior frontal, left dorsolateral prefrontal and bilateral temporal regions. In contrast, increased SSVEP amplitude and decreased SSVEP latency were observed within occipital regions. The observed SSVEP latency increases within frontal and temporal cortical regions are suggestive of increased localised inhibitory processes within regions reciprocally connected to subcortical limbic structures. Occipital SSVEP latency decreases are suggestive of increased excitatory activity. SSVEP amplitude increases within occipital regions may be associated with an attentional shift from external to internal environment. The current findings provide further support for the involvement of frontal, anterior temporal, and occipital cortical regions during anticipatory anxiety, and suggest that both excitatory and inhibitory processes are associated with AA alterations.