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Functional anatomy of cognitive development: fMRI of verbal fluency in children and adults.

OBJECTIVE: To identify age-dependent activation patterns of verbal fluency with functional MRI (fMRI). BACKGROUND: Few fMRI language studies have been performed in children, and none provide comparison data to adult studies. Normative data are important for interpretation of similar studies in patients with epilepsy. METHODS: A total of 10 normal children (5 boys, 5 girls; mean age, 10.7 years; range, 8.1 to 13.1 years) and 10 normal adults (5 men, 5 women; mean age, 28.7 years; range, 19.3 to 48 years) were studied on a 1.5-T Signa MRI scanner using BOLD echo planar imaging of the frontal lobes with a verbal fluency paradigm, covert word generation to letters. Studies were analyzed with a cross-correlation algorithm (r = 0.7). A region-of-interest analysis was used to determine the extent, magnitude, and laterality of brain activation. RESULTS: Children and adults activated similar regions, predominantly in left inferior frontal cortex (Broca's area) and left middle frontal gyrus (dorsolateral prefrontal cortex). Children had, on average, 60% greater extent of activation than adults, with a trend for greater magnitude of activation. Children also had significantly more right hemisphere and inferior frontal gyrus activation than adults. CONCLUSIONS: In a test of verbal fluency, children tended to activate cortex more widely than adults, but activation patterns for fluency appear to be established by middle childhood. Thus, functional MRI using verbal fluency paradigms may be applied to pediatric patient populations for determining language dominance in anterior brain regions. The greater activation found in children, including the right inferior frontal gyrus, may reflect developmental plasticity for the ongoing organization of neural networks, which underlie language capacity.

Adolescent↗

Cortical localization of reading in normal children: an fMRI language study.

BACKGROUND: fMRI provides a noninvasive means of identifying the location and organization of neural networks that underlie cognitive functions. OBJECTIVE: To identify, using fMRI, brain regions involved in processing written text in children. METHODS: The authors studied nine normal right-handed native English-speaking children, aged 10.2 years (range 7.9 to 13.3 years), with two paradigms: reading Aesop's Fables and "Read Response Naming" (reading a description of an object that was then silently named). Data were acquired using blood oxygen level-dependent fMRI. Group data were analyzed with statistical parametric mapping; individual data sets were analyzed with a region-of-interest approach from individual study t maps. The number of activated pixels was determined in brain regions and an asymmetry index (AI = [L - R]/[L + R]) calculated for each region. RESULTS: The authors found strong activation in the left middle temporal gyrus and left midfrontal gyrus and variable activation in left inferior frontal gyrus for both reading tasks in the group analysis (z > 5.5 to 9.1). All subjects had strong left-sided lateralization for both tasks in middle/superior temporal gyrus, inferior frontal gyrus, and middle frontal gyrus (AI = 0.76 to 1.0 for t = 4). Reading Fables activated twice as many pixels in temporal cortex as the Read Response Naming task; activation in dorsolateral prefrontal cortex was similar for both tasks. Small homologous right middle temporal region activation was seen with reading a fable. CONCLUSIONS: The neural networks that process reading appear to be lateralized and localized by middle to late childhood. Reading text paradigms may prove useful for identifying frontal and temporal language-processing areas and for determining language dominance in children experiencing epilepsy or undergoing tumor surgery.

Brain Mapping↗

DARPP-32, a phosphoprotein enriched in dopaminoceptive neurons bearing dopamine D1 receptors: distribution in the cerebral cortex of the newborn and adult rhesus monkey.

DARPP-32, a dopamine (DA) and cAMP-regulated phosphoprotein, is associated with dopaminoceptive neurons bearing D-1 receptors in the basal ganglia. The present study addressed the distribution of DARPP-32 in the primate cerebral cortex and its putative association with D-1 receptor laden cells in this structure. DARPP-32-like immunoreactive (LIR) neurons were examined in the cerebral cortex of 3-day-old (P3), 6-week-old (P42), and adult rhesus monkeys. In the younger cases, a large number of DARPP-32 positive neurons, with the morphological characteristics of pyramidal cells, were observed throughout the cortex, in layers V-VI, and to a lesser extent in layer II and uppermost layer III. In the parietal, insular, temporal, and occipital cortices, DARPP-32 positive neurons were arranged in a monolayer in layer Va. They were often clustered in small groups with a bundling of their dendrites. In the primary motor cortex, Betz cells were among the labeled population. In the association and somatosensory areas, the basal dendrites of DARPP-32 positive neurons and the prominent tufting of their apical dendrites in layer I contributed to an essential bilaminar pattern resembling the distribution reported for DA afferents and D-1 receptors in these areas. The prominence and widespread distribution of DARPP-32 positive neurons in layer V may be a specialization of primate cortex since such cells are found only in restricted locations in rodents. The literature on the connections of the cerebral cortex suggests that a large number of the DARPP-32 positive neurons in layer VI and perhaps even in layer Va may be corticothalamic neurons. An important developmental observation was the presence of DARPP-32-LIR neurons in the white matter. They were prominent in the neonates but could not be seen in the adult. Their location as well as their type and shape were reminiscent of interstitial neurons. In the adult monkeys, the distribution of DARPP-32-LIR neurons was more circumscribed: they were numerous in the ventral temporal gyrus and in areas related to the limbic system: caudal orbitofrontal cortex, insula, temporal pole, entorhinal, and anterior cingulate cortex. Weak labeling was detected in layer Va of the superior temporal and parietal cortex, in some prefrontal areas (10, 13, and medial 9), and in the premotor and supplementary motor cortex; in adults, unlike neonates, few DARPP-32-LIR neurons were present in the dorsolateral prefrontal cortex, the primary motor or the primary visual or prestriate cortices.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

Postnatal maturation of the layer III pyramidal neurons in the human prefrontal cortex: a quantitative Golgi analysis.

In this study we examined the morphological maturation of the basal dendritic field of layer III pyramidal neurons located in the human dorsolateral prefrontal cortex in subjects ranging from 7.5 months after birth up to 27 years. The sections were stained with the Golgi-Cox method and the three-dimensional branching pattern was measured with a semi-automatic dendrite measuring system. Results show a rapid growth phase of the dendritic field from 7.5 months after birth up to one year. A marked increase in total dendritic length is observed, for which elongation of the terminal segments, longer intermediate segments and an increase in number of segments is an explanation. The dendritic length appears to have stabilized after one year, leading us to conclude that the postnatal morphological maturation of the layer III pyramidals does not continue well into childhood, but is completed at a much younger age. Additionally we analyzed the effect of varying section thickness on dendritic parameters and found no tendency for higher dendritic values with increasing section thickness for the range of thickness values of the histological sections used.

Adolescent↗

Identification of protein biomarkers for schizophrenia and bipolar disorder in the postmortem prefrontal cortex using SELDI-TOF-MS ProteinChip profiling combined with MALDI-TOF-PSD-MS analysis.

This paper describes the high-throughput proteomic analysis of the dorsolateral prefrontal cortex (DLPFC) from schizophrenia (SCHIZ), bipolar (BD), and normal control cohorts from the Harvard Brain Tissue Resource Center performed using ProteinChip technology based on the surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS). The resultant profiles were utilized in classification-tree algorithms for selection of protein biomarker peaks contributing maximally to the differentiation between the examined diagnostic cohorts. Twenty-four such protein biomarker peaks were identified. All of them had lower levels in the SCHIZ cohort as compared to the BD cohort. Also, 21 of these peaks were down-regulated in the SCHIZ cohort vs. the control cohort, and 7 peaks were up-regulated in the BD cohort vs. the control cohort. The proteins constituting these biomarker peaks were recognized via matrix-assisted laser desorption time of flight/postsource decay mass spectrometry (MALDI-TOF-PSD-MS). These proteins represent a wide range of functional groups involved in cell metabolism, signaling cascades, regulation of gene transcription, protein and RNA chaperoning, and other aspects of cellular homeostasis. Finally, after statistical evaluation suggesting that the selected protein biomarkers are not significantly impacted by epidemiological/tissue storage parameters (although, influence of antipsychotic and mood stabilizing drugs could not be fully excluded), the ProteinChip-based profiling was engaged again to demonstrate that the detected SCHIZ-associated changes in the levels of our protein biomarkers could also be seen in DLPFC samples from the brain collection of the Mount Sinai Medical School/Bronx Veteran Affairs Medical Center. This study demonstrates the usefulness of ProteinChip-based SELDI-TOF protein profiling in gaining insight into the molecular pathology of SCHIZ and BD as it points to changes in protein levels characterizing these diseases.

Aged↗

Implementation of visuospatial cues in response selection.

We used functional magnetic resonance imaging to examine neuronal activity reflecting the dynamic interplay of external and internal guidance of action. Participants performed a choice reaction time task based on spatial visual cues with their right and left middle and index finger. In a given trial, the cue either fully determined the motor response (no-selection) or indicated the number and location of alternative responses (selection). Compared with fully determined responses, the selection among (two to four) alternative responses activated a widespread bilateral parieto-premotor-prefrontal cortical network along with the cerebellum. Within this network, task-related activity patterns allowed to delineate two sets of brain areas. In the anterior part of rostral dorsal premotor cortex (PMd), the rostral cingulate and supplementary motor area and the right dorsolateral prefrontal cortex, the increase in activity was independent of spatially defined restrictions. In contrast, there was an additional increase in activity in the posterior part of rostral PMd, superior parietal lobule and parieto-occipital sulcus bilaterally as well as in the right anterior intraparietal sulcus, when the visuospatial cue imposed specific constraints on response selection. We propose that the latter set of dorsal parieto-frontal areas subserves rapid implementation of spatial information during visually guided response selection.

Adult↗

Neural circuits subserving the retrieval of stems and grammatical features in regular and irregular verbs.

Many languages, including English and Spanish, feature regular (dance --> danced) and irregular (catch --> caught) inflectional systems. According to psycholinguistic theories, regular and irregular inflections are instantiated either by a single or by two specialized mechanisms. Those theories differ in their assumptions concerning the underlying information necessary for the processing of regular verbs. Whereas single mechanism accounts have stated an increased involvement of phonological processing for regular verbs, dual accounts emphasize the prominence of grammatical information. Using event-related functional magnetic resonance imaging, we sought to delineate the brain areas involved in the generation of complex verb forms in Spanish. This language has the advantage of isolating specific differences in the regular-irregular contrasts in terms of the number of stems associated with a verb while controlling for compositionality (regular and irregular verbs apply suffixes to be inflected). The present study showed that areas related to grammatical processing are active for both types of verbs (left opercular inferior frontal gyrus). In addition, major differences between regular and irregular verbs were also observed. Several areas of the prefrontal cortex were selectively active for irregular production, presumably reflecting their role in lexical retrieval (bilateral inferior frontal area and dorsolateral prefrontal cortex). Regular verbs, however, showed increased activation in areas related to grammatical processing (anterior superior temporal gyrus/insular cortex) and in the left hippocampus, the latter possibly related to a greater implication of the phonological loop necessary for the reutilization of the same stem shared across all forms in regular verbs.

Adult↗

Hemodynamic differences in the activation of the prefrontal cortex: attention vs. higher cognitive processing.

Both simple attention tasks (e.g. letter cancellation) and most tasks of higher cognitive processing (e.g. word generation) are known to activate the dorsolateral prefrontal cortex (PFC). While attention and higher cognitive processing differ phenomenologically, with attention tasks requiring great subjective effort despite their simplicity, possible physiological differences in the activation of the PFC between the two types of cognitive processing have remained uninvestigated. Hemodynamic changes in the PFC during activation due to tasks of attention and those of higher cognitive processing were examined using near-infrared spectroscopy in 10 Japanese and 10 American healthy adults. In tasks of higher cognitive processing, which included both verbal and non-verbal tasks, the concentration of oxygenated hemoglobin ([HbO2]) increased, and that of deoxygenated hemoglobin ([HbR]) decreased, with an increase in the tissue hemoglobin saturation (THS). In tasks of attention, which consisted of the letter cancellation and continuous performance test, both [HbO2] and [HbR] increased, with no significant changes in the THS observed. The distinctive patterns of hemodynamic changes were not affected by the factors of task difficulty or language. The change in [HbR] may be a physiological marker of the prefrontal lobe activation that discriminates between attention and higher cognitive processing. The increase in [HbR] suggests increased oxygen consumption of the PFC during tasks of attention, which might be related to the disproportionately great subjective effort associated with sustained attention. The physiological alteration in hemodynamic patterns according to changes in cognition needs to be examined in subjects with prefrontal lobe dysfunction, such as schizophrenia and mood disorder.

Adolescent↗

Gene expression of metabolic enzymes and a protease inhibitor in the prefrontal cortex are decreased in schizophrenia.

Microarray expression studies have reported decreased mRNA expression of histidine triad nucleotide-binding protein (HINT1) and cytosolic malate dehydrogenase (MDH1) in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Microarray results for neuroserpin (SERPINI1) mRNA in the DLPFC have reported increased and decreased expression in individuals with schizophrenia. The relative abundances of HINT1, MDH1, and SERPINI1 mRNA in the DLPFC in individuals with schizophrenia and controls were measured by real-time quantitative polymerase chain reaction (Q-PCR) and for HINT1 expression by in situ hybridization. The Q-PCR results were compared by analysis of covariance between individuals with schizophrenia and controls. Gene expression levels for HINT1, MDH1, and SERPINI1 were significantly different between the groups. The male individuals with schizophrenia compared to male controls showed reductions by 2.8- to 3.7-fold of HINT1, neuroserpin, and MDH1 by Q-PCR. The decreases in mRNA abundance for MDH1 (P = 0.006), HINT1 (P = 0.050), and neuroserpin (P = 0.005) in DLPFC of male individuals with schizophrenia is consistent with prior reports. HINT1 mRNA was reduced significantly by 34% in layer VI. Though there were no significant interactions with gender, gene expression between female patients and the female control group did not differ. These results confirm earlier reports and suggest abnormalities of specific genes related to metabolic and protease activities in the DLPFC might be considered as part of a molecular pathway in male patients with schizophrenia.

Adult↗

Elevated levels of endocannabinoids and CB1 receptor-mediated G-protein signaling in the prefrontal cortex of alcoholic suicide victims.

BACKGROUND: Alcoholism is often comorbid with mood disorders and suicide. We recently reported an upregulation of CB(1) receptor-mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who died by suicide. In the present study, we sought to determine whether the changes in depressed suicides would also be present in alcoholic suicides and whether the endocannabinoid (EC) system plays a role in suicide in alcoholism. METHODS: The density of CB(1) receptor and its mediated [(35)S]GTP gamma S signaling were measured in the DLPFC of alcoholic suicides (AS) (n = 11) and chronic alcoholics (CA) (n = 11). The levels of ECs were measured by a liquid chromatograph/mass spectrometry. RESULTS: The CB(1) receptor density was higher in AS compared with the CA group in the DLPFC. Western blot analysis confirmed a greater immunoreactivity of the CB(1) receptor in AS. The CB(1) receptor-mediated [(35)S]GTP gamma S binding indicated a greater signaling in AS. Higher levels of N-arachidonyl ethanolamide and 2-arachidonylglycerol were observed in the DLPFC of AS. CONCLUSIONS: The elevated levels of ECs, CB(1) receptors, and CB(1) receptor-mediated [(35)S]GTP gamma S binding strongly suggest a hyperactivity of endocannabinoidergic signaling in AS. EC system may be a novel therapeutic target for the treatment of suicidal behavior.

Adolescent↗

Evidence for premotor cortex activity during dynamic visuospatial imagery from single-trial functional magnetic resonance imaging and event-related slow cortical potentials.

A strong correspondence has been repeatedly observed between actually performed and mentally imagined object rotation. This suggests an overlap in the brain regions involved in these processes. Functional neuroimaging studies have consistently revealed parietal and occipital cortex activity during dynamic visuospatial imagery. However, results concerning the involvement of higher-order cortical motor areas have been less consistent. We investigated if and when premotor structures are active during processing of a three-dimensional cube comparison task that requires dynamic visuospatial imagery. In order to achieve a good temporal and spatial resolution, single-trial functional magnetic resonance imaging (fMRI) and scalp-recorded event-related slow cortical potentials (SCPs) were recorded from the same subjects in two separate measurement sessions. In order to reduce inter-subject variability in brain activity due to individual differences, only male subjects (n = 13) with high task-specific ability were investigated. Functional MRI revealed consistent bilateral activity in the occipital (Brodmann area BA18/19) and parietal cortex (BA7), in lateral and medial premotor areas (BA6), the dorsolateral prefrontal cortex (BA9), and the anterior insular cortex. The time-course of SCPs indicated that task-related activity in these areas commenced approximately 550-650 ms after stimulus presentation and persisted until task completion. These results provide strong and consistent evidence that the human premotor cortex is involved in dynamic visuospatial imagery.

Adult↗

The role of the inferior frontal junction area in cognitive control.

Cognitive control processes refer to our ability to coordinate thoughts and actions in accordance with internal goals. In the fronto-lateral cortex such processes have been primarily related to mid-dorsolateral prefrontal cortex (mid-DLPFC). However, recent brain-imaging and meta-analytic studies suggest that a region located more posterior in the fronto-lateral cortex plays a pivotal role in cognitive control as well. This region has been termed the inferior frontal junction area and can be functionally and structurally distinguished from mid-DLPFC.

Animals↗

Storage and executive processes in the frontal lobes.

The human frontal cortex helps mediate working memory, a system that is used for temporary storage and manipulation of information and that is involved in many higher cognitive functions. Working memory includes two components: short-term storage (on the order of seconds) and executive processes that operate on the contents of storage. Recently, these two components have been investigated in functional neuroimaging studies. Studies of storage indicate that different frontal regions are activated for different kinds of information: storage for verbal materials activates Broca's area and left-hemisphere supplementary and premotor areas; storage of spatial information activates the right-hemisphere premotor cortex; and storage of object information activates other areas of the prefrontal cortex. Two of the fundamental executive processes are selective attention and task management. Both processes activate the anterior cingulate and dorsolateral prefrontal cortex.

Animals↗

Representation of attitudinal knowledge: role of prefrontal cortex, amygdala and parahippocampal gyrus.

It has been proposed that behavior is influenced by representations of different types of knowledge: action representations, event knowledge, attitudes and stereotypes. Attitudes (representations of a concept or object and its emotional evaluation) allow us to respond quickly to a given stimulus. In this study, we explored the representation and inhibition of attitudes. We show that right dorsolateral prefrontal cortex mediates negative attitudes whereas left ventrolateral prefrontal cortex mediates positive attitudes. Parahippocampal regions and amygdala mediate evaluative processing. Furthermore, anxiety modulates right dorsolateral prefrontal activation during negative attitude processing. Inhibition of negative attitudes activates left orbitofrontal cortex: a region that when damaged is associated with socially inappropriate behavior in patients. Inhibition of positive attitudes activates a brain system involving right inferior frontal gyrus and bilateral anterior cingulate. Thus, we show that there are dissociable networks for the representation and inhibition of attitudes.

Adult↗

The prefrontal cortex in sleep.

Experimental data indicate a role for the prefrontal cortex in mediating normal sleep physiology, dreaming and sleep-deprivation phenomena. During nonrandom-eye-movement (NREM) sleep, frontal cortical activity is characterized by the highest voltage and the slowest brain waves compared to other cortical regions. The differences between the self-awareness experienced in waking and its diminution in dreaming can be explained by deactivation of the dorsolateral prefrontal cortex during REM sleep. Here, we propose that this deactivation results from a direct inhibition of the dorsolateral prefrontal cortical neurons by acetylcholine, the release of which is enhanced during REM sleep. Sleep deprivation influences frontal executive functions in particular, which further emphasizes the sensitivity of the prefrontal cortex to sleep.

Journal Article↗

Dopamine modulation of neuronal function in the monkey prefrontal cortex.

We developed a brain slice preparation that allowed us to apply whole-cell recordings to examine the electrophysiological properties of identified synapses, neurons, and local circuits in the dorsolateral prefrontal cortex (DLPFC) of macaque monkeys. In this article, we summarize the results from some of our recent and current in vitro studies in the DLPFC with special emphasis on the modulatory effects of dopamine (DA) receptor activation on pyramidal and nonpyramidal cell function in superficial layers in DLPFC areas 46 and 9.

Animals↗

Spatial distribution and density of prefrontal cortical cells projecting to three sectors of the premotor cortex.

The spatial distribution of prefrontal cortical cells projecting to three different sectors in the premotor cortex was examined. The cells projecting to the three sectors were distributed in separate regions in the dorsolateral prefrontal cortex with a small overlap. Cells projecting to the ventral sector were distributed in the lower bank of the principal sulcus (PS). Those projecting to the restro-dorsal sector were located near the superior limb of the arcuate sulcus, and in the dorsal convexity and upper bank of the PS. Cells projecting to the caudo-dorsal sector were observed in the upper bank of the PS and in the area 8a. These findings suggest that each of the three sectors of the premotor cortex receive different sets of information from the prefrontal cortex.

Amidines↗

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↗