Monkeys were trained to draw triangles, squares, trapezoids and inverted triangles while we recorded the activity of small ensembles of neurons in caudal area 46 and areas 5 and 2 of parietal cortex. 
We performed RT-PCR to quantify DARPP-32 mRNA from brain samples (Brodmann area 46) donated by the Stanley Medical Research Institute (SMRI, Array Collection): 35 from unaffected controls (UC), 35 from patients with schizophrenia (SCZ), and 35 with bipolar disorder (BP). SNP genotyping was conducted by PCR on DNA obtained from Brodmann area 46.
An electron microscopic analysis has been carried out on the effects of age on the numerical density of both excitatory (asymmetric) and inhibitory (symmetric) synapses in the neuropil of layers 2/3 and of layer 5 in area 46 from the frontal cortex of behaviorally tested rhesus monkeys. However synapse loss is not the only factor causing cognitive impairment, since in previous studies of area 46 we have found that age-related alteration in myelin in this frontal area also significantly contributes to cognitive decline.
We performed optical recording with a voltage-sensitive dye (RH482) in brain slices obtained from the principal sulcal region (area 46) of macaque monkeys.
METHODS: RNA samples from the dorsolateral prefrontal cortex (Brodmann area 46) consisting of individuals with schizophrenia (SZ), bipolar disorder (BPD), and control subjects were tested on the Codelink Human 20K Bioarray platform.
Microarray studies with post-mortem prefrontal cortex (Brodmann's area 46/10) tissue require larger sample sizes.
The rTMS target was determined with the "standard procedure" for the first week and with a dedicated navigation system as the left Brodmann area 46 for the second week.
Area 45A borders dorsally, in the proximity of the principal sulcus, with area 46 and, ventrally, with area 12.
Whole cell patch-clamp recordings were employed to characterize the electrophysiological properties of layer 5 pyramidal cells in slices of the prefrontal cortex (area 46) of the rhesus monkey.
Our focus was on cortical fields that send strong projections to extrastriate cortex, including the dorsal and ventral subdivisions of area 8A, area 46 and area 6d.
In the present study, we selected bilateral Brodmann's area 46 as region of interest and analyzed the differences in the DLPFC functional connectivity pattern between 17 patients with first-episode schizophrenia (FES) and 17 matched controls using resting-state fMRI.
MATERIALS AND METHODS: Eight adult male African green monkeys were treated with saline or phencyclidine (0.3 mg/kg BID x 14 days) and, after 8 days drug-free, perfused and fixed, and the principal sulcus was collected (Walker's area 46) for immunohistochemical analysis. Additionally, there was no change in the total density or laminar location of parvalbumin-containing or calretinin-containing cell bodies in area 46.
A comparison of the neural activity associated with these conditions as measured by functional MRI showed that conscious perception is associated with spatially specific activity in the mid-dorsolateral prefrontal cortex (area 46).
METHODS AND RESULTS: To address this problem, the effects of chronic ethanol self-administration in male cynomolgus monkeys on GABA(A) receptor subunit mRNA expression was studied in 3 frontal cortical fields: orbitofrontal cortex (OFC; area 13), anterior cingulate cortex (ACC; area 24), and the dorsolateral prefrontal cortex (DLPFC; area 46).
A postmortem brain expression study showed up-regulation of mRNA isoform 2 in the prefrontal cortex (Brodmann's area 46) of patients with schizophrenia.
It was shown that prefrontal area 46 and parietal areas VIP and 7a occupy a central position between the different clusters in the visuo-tactile network.
Here, we examined potential neurobiological substrates of this effect using intracellular loading and morphometric analyses to test the possibility that the cognitive benefits of hormone treatment are associated with structural plasticity in layer III pyramidal cells in PFC area 46.
area 46, located rostrolateral to area 8Av, has substantial connections with the medial extrastriate areas (DM, DA, and area 7) and with MT, while the cortex lateral to 8Av (area 12/45) projects primarily to MT and to the MTc.
The main finding was that right DLPFC (Brodmann area 46/10) activity was greater for low- than for high-confidence decisions in both tasks, demonstrating a general role in decision making.
The results were compared with similar data from prefrontal area 46 in the same subjects. However, the magnitude of the reductions in the density of GABA membrane transporter-1-immunoreactive cartridges in area 42 of the subjects with schizophrenia was not significantly smaller than those in area 46.
mRNA samples provided by the Stanley Foundation Array Collection were derived from the dorsolateral prefrontal cortex (Brodmann area 46) of 35 bipolar, 35 schizophrenic, and 35 control subjects.
For the centromedian nucleus, positive correlation with the dorsolateral prefrontal area 46 in the right hemisphere was significantly weaker in patients than in healthy subjects.
The theory was applied to measuring 3D spatial complexity in the apical and basal dendritic trees of two functionally distinct types of macaque monkey neocortical pyramidal neurons: long corticocortical projection neurons from superior temporal cortex to area 46 of the prefrontal cortex (PFC), and local projection neurons within area 46 of the PFC.
METHODS: Quantitative PCR (q-PCR) was used to determine relative mRNA levels in dorsolateral prefrontal cortex (Brodmann's area 46) samples donated by the Stanley Medical Research Institute (SMRI).
The cells projecting to the SEF and pre-SMA were mainly distributed in the upper and lower banks of the principal sulcus (area 46), with little overlap.
mRNA samples provided by the Stanley Foundation Array Collection were derived from the dorsolateral prefrontal cortex (Brodmann area 46) of 23 completed suicides and 23 control subjects.
METHOD: Spine density and other dendritic measures were made for pyramidal neurons in layers 5 and 6 of prefrontal area 46 in the brains of deceased subjects with schizophrenia, subjects with other psychiatric disorders, and normal comparison subjects.
This region closely corresponds to Brodmann area 46 as defined by recent cytoarchitectonic studies.
Lesion studies and functional magnetic resonance imaging (fMRI) studies suggest that the human DLPFC is located in area 46 of Brodmann.
Whereas ventral area 46 was most densely labeled from the forelimb region, only sparse labeling from the hindlimb region was observed in this prefrontal area. The present results suggest the importance of ventral area 46 in the cognitive control of forelimb movements..
Many age-related declines in cognitive function are attributed to the prefrontal cortex, area 46 being especially critical. Yet in normal aging, studies indicate that neurons are not lost in area 46, suggesting that impairments result from more subtle processes. By using a density-map method derived from condensed-matter physics, we quantified microcolumns in area 46 of seven young and seven aged rhesus monkeys that had been cognitively tested.
We employed Western blot and real-time reverse transcriptase polymerase chain reaction analyses to compare prefrontal (area 46) and occipital (area 17) cortical levels of calcyon and NCS-1 proteins and mRNAs between schizophrenia (n = 37) and control (n = 30) cohorts from the Brain Collection of the Mount Sinai Medical School/Bronx Veterans Administration Medical Center.
In an attempt to analyse the organization of the prefrontal outflow from area 46 toward the frontal motor-related areas, we investigated the pattern of projections involving the higher-order motor-related areas, such as the presupplementary motor area (pre-SMA) and the rostral cingulate motor area (CMAr). (i) Only a few neurons in area 46 were retrogradely labelled from the pre-SMA and CMAr; (ii) terminal labelling from area 46 occurred sparsely in the pre-SMA and CMAr; (iii) a dual labelling technique revealed that the sites of overlap of anterograde labelling from area 46 and retrograde labelling from the pre-SMA and CMAr were evident in the rostral parts of the dorsal and ventral premotor cortices (PMdr and PMvr); (iv) and tracer injections into the PMdr produced neuronal cell labelling in area 46 and terminal labelling in the pre-SMA and CMAr. The present results indicate that a large portion of the prefrontal signals from area 46 is not directly conveyed to the pre-SMA and CMAr, but rather indirectly by way of the PMdr and PMvr. This suggests that area 46 exerts its major influence on the cortical motor system via these premotor areas..
In contrast, neuronal number was strikingly preserved in an adjoining prefrontal cortical region also associated with working memory, area 46, and in the component of the nucleus basalis projecting to this region.
METHOD: The densities and laminar distribution of axon initial segments with 5-HT(1A)-like immunoreactivity were assessed in postmortem tissue from the prefrontal cortex (Brodmann's area 46) of 14 matched triads of subjects with schizophrenia, subjects with major depressive disorder, and comparison subjects with no psychiatric disorder.
It has been suggested that they are associated with activations in the dorsal prefrontal cortex (area 46).
Using an antibody against the spine-associated protein, spinophilin, spine numbers were estimated in layer I of area 46 and in layer I of the opercular portion of area V1 (V1o). Spine numbers in layer I of area 46 were significantly increased (55%) in the ovariectomy + estrogen group compared to the ovariectomy + vehicle group, yet spine numbers in layer I of area V1o were equivalent across the two groups.
In area 46, reductions in cortical width in layers II (18%) and VI (35%) were not accompanied by neuronal loss. Glial density was increased in deeper layers, reaching significance in layer VI (68%) of area 9 and in layer V (75%) of area 46; glial number was not altered. Thus, area 46 exhibited marked cortical thinning without apparent neuronal degeneration, whereas in area 9 neuronal loss was pronounced, consistent with an advanced phase of cortical pathology.
We extended that finding by comparing the density of microtubule-associated protein 2-immunoreactive ICWMs in deficit schizophrenia (N = 3), nondeficit schizophrenia (N = 4), and control (N = 5) subjects, using postmortem tissue from the dorsolateral prefrontal cortex (Brodmann area 46).
We used transneuronal transport of neurotropic viruses to examine the topographic organization of circuits linking the cerebellar cortex with the arm area of the primary motor cortex (M1) and with area 46 in dorsolateral prefrontal cortex of monkeys. In contrast, transneuronal transport of rabies from area 46 revealed that it receives input from Purkinje cells located primarily in Crus II of the ansiform lobule. Thus, both M1 and area 46 are the targets of output from the cerebellar cortex. Anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 (HSV1) revealed that neurons in the arm area of M1 project via the pons to granule cells primarily in lobules IV-VI, whereas neurons in area 46 project to granule cells primarily in Crus II. Similarly, the regions of the cerebellar cortex that receive input from area 46 are the same as those that project to area 46.
Thus, we examined the relative densities, laminar distributions, and lengths of presynaptic chandelier axon cartridges immunoreactive for the GABA membrane transporter 1 (GAT1) or the calcium-binding protein parvalbumin (PV) and of postsynaptic pyramidal neuron AIS immunoreactive for the GABA(A) receptor alpha(2) subunit (GABA(A) alpha(2)) in PFC area 46 of 38 rhesus monkeys (Macaca mulatta).
The heterotopic connections of F7 originate mainly from F2, with smaller contingent from pre-supplementary motor area (pre-SMA, F6), area 8 (frontal eye fields), and prefrontal cortex (area 46), while those of F2 originate from F7, with smaller contributions from ventral premotor areas (F5, F4), SMA-proper (F3), and primary motor cortex (M1).
We analyzed how such changes affect a specific subpopulation of cortical neurons forming long corticocortical projections from the superior temporal cortex to prefrontal area 46.
Brodmann area 46, were tested using different paradigms of reflexive saccades (gap and overlap tasks), intentional saccades (antisaccades, memory-guided and predictive saccades) and smooth pursuit movements.
The effect of aging on myelin sheaths in the rhesus monkey was studied in the vertical bundles of nerve fibers that traverse monkey cerebral cortex in primary visual area 17 and prefrontal area 46. The increase in paranodal frequency with age is 57% in area 17 and 90% in area 46.
CNS-focused cDNA microarrays were used to examine gene expression profiles in dorsolateral prefrontal cortex (dlPFC, area 46) from seven individual sets of age- and post-mortem interval-matched male cocaine abusers and controls.
Increased apoD levels were observed in the lateral prefrontal cortex (Brodmann area 46) in both schizophrenia (46%) and bipolar disorder (111%), and in the orbitofrontal cortex (Brodmann Area 11) (44.3 and 37.9% for schizophrenia and bipolar disorder, respectively).
Multiple injections of tracers were performed in 15 macaque monkeys, aimed toward primary motor area (M1), pre-supplementary motor area (pre-SMA), SMA-proper, rostral (PMd-r) and caudal (PMd-c) parts of the dorsal premotor cortex (PM), rostral (PMv-r) and caudal (PMv-c) parts of the ventral PM, and superior and inferior parts of area 46. The same territories were labeled after injection in area 46, but in addition numerous labeled neurons were found in the most ventral part of the claustrum. A comparable local segregation was observed for the two subdivisions of area 46, whereas there was more local overlap among the subareas of PM. The projections from the claustrum to the multiple subareas of the motor cortex and to area 46 arise from largely overlapping territories, with, however, some degree of local segregation..
The mean total length of serotonin transporter-immunoreactive axons per unit area was unchanged in layers 2 and 4 of area 46 in the depressed suicide subjects compared to controls, but was significantly (P < 0.01) decreased by 24% in layer 6 in the depressed suicide group.
Because the alpha(2) subunit of the GABA(A) receptor is preferentially localized at pyramidal neuron AIS, we quantified alpha(2) subunit immunoreactive AIS in tissue sections containing prefrontal cortex area 46 from 14 matched triads of subjects with schizophrenia, subjects with major depression and control subjects.
area 46 of the prefrontal cortex in non-human primates receives direct inputs from several association areas, among them the cortical regions lining the superior temporal sulcus. We examined whether projection neurons providing such a corticocortical projection differ in their dendritic morphology from pyramidal neurons projecting locally within area 46. Total dendritic length, numbers of segments, numbers of spines, and spine density were analyzed in layer III pyramidal neurons forming long projections (from the superior temporal cortex to prefrontal area 46), as well as local projections (within area 46). Sholl analysis was also used to compare the complexity of these two groups of neurons.Our results demonstrate that long corticocortical projection neurons connecting the temporal and prefrontal cortex have longer, more complex dendritic arbors and more spines than pyramidal neurons projecting locally within area 46.
We used retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 to examine the extent and organization of basal-ganglia-thalamocortical projections to five regions of prefrontal cortex in the cebus monkey (Cebus apella): medial and lateral area 9 (9m and 9l), dorsal and ventral area 46 (46d and 46v) and lateral area 12 (12l).
RESULTS: Nonoverlapping memory effects were evident: low (n = 4; propofol concentration 523 +/- 138 ng/ml; 44 +/- 13% decrement from baseline memory) and high (n = 7; 829 +/- 246 ng/ml; 87 +/- 6% decrement from baseline) groups differed in rCBF reductions primarily in right-sided prefrontal and parietal regions, close to areas activated in the baseline memory task, particularly R dorsolateral prefrontal cortex (Brodmann area 46; x, y, z = 51, 38, 22).
In area 46, the density of parvalbumin- immunoreactive puncta in the superficial and middle layers was extremely low in the newborn animals, then increased more than 10-fold to adult levels, which were achieved by 3 to 4 years of age. Developmental changes of parvalbumin-immunoreactive puncta in area 9 were similar to those in area 46.
Compared to controls, bipolar patients had significantly lower levels of CaMKII alpha mRNA in laminae I-VI of Brodmann's area 9 and laminae I-III and VI of area 46.
Using immunocytochemistry and Western immunoblotting, we compared the localization and levels of group II mGluRs in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects. Consistent with previous reports, we found that immunolabeling of group II mGluRs is prominent in Brodmann's area 46. We conclude that while the function of group II mGluRs in Brodmann's area 46 of dorsolateral prefrontal cortex may be altered in patients with schizophrenia, this is not evident at the level of protein expression using an antibody against mGluR2 and mGluR3..
In the rhesus monkey, the myelin sheaths of nerve fibers in area 46 of prefrontal cortex and in splenium of the corpus callosum show age-related alterations in their structure. To quantify the frequency of the age-related alterations in myelin, transversely sectioned nerve fibers from the splenium of the corpus callosum and from the vertical bundles of nerve fibers within area 46 were examined in electron photomicrographs. In area 46, the age-related alterations also significantly correlate (P < 0.001) with an overall assessment of impairment in cognition, i.e., the cognitive impairment index, displayed by individual monkeys.
In this study, reliable methods for measuring an estimate of area 46 (estimate referred to as area 46(e)), as defined by 'Cereb. Cortex 5 (1995) 323', were developed and used to examine relationships between area 46(e) volumes, working memory, and symptom severity in 23 male patients and 23 healthy male comparison subjects. Patients performed more poorly than healthy reference subjects on all cognitive measures including measures of spatial and non-spatial working memory, but showed no significant corresponding deficits in area 46(e) volumes or whole brain volumes. Moreover, there were no significant relationships between symptom severity and area 46(e) volumes.
Although there is significant thinning of layer 1 with age in both occipital area 17 and prefrontal area 46 of the rhesus monkey, there are no significant age-related changes in the numbers of neurons, astrocytes, or microglia and oligodendrocytes in this layer.
In contrast, the selection of one location, according to its order, was associated with a distinct frontoparietal network, including dorsolateral prefrontal area 46, ventrolateral prefrontal cortex and anterior cingulate cortex and medial parietal cortex. We suggest a general role of the dorsolateral prefrontal area 46 in attentional selection, including selection from within working memory..
In layer V of the prefrontal cortex (Brodman's area 46) in the chimpanzee fetus, and in layer Vb of the cingulate cortex in adult macaque monkeys, no spindle neurons were observed.
RESULTS: Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance.
RESULTS: Relative to those of comparison subjects, the mean levels of [ (3)H]pirenzepine binding were significantly lower in Brodmann's areas 9 and 46 of the schizophrenia patients not treated with benztropine mesylate (18% lower in Brodmann's area 9 and 21% lower in Brodmann's area 46) and in all four examined regions of the patients who had received benztropine (51%-64% lower).
Women with Parkinson's disease had 87% higher Fdopa uptake in the right dorsolateral prefrontal cortex (area 46) compared with men with Parkinson's disease, whereas there was no sex difference in the control group (sex x disease interaction, P = 0.03).
To test this hypothesis, we employed the DNA array technique to compare the mRNA expression profiles of three neocortical subregions of the human brain: prefrontal cortex (area 46), motor cortex (Area 4) and visual cortex (Area 17).
Lesions were limited to small areas within either the dorsolateral (Brodmann's area 46/9) or ventromedial (posterior part of the gyrus rectus) cortices.
Similar morphological changes with age occur in layer 1 of prefrontal cortex of these same monkeys, but in area 46 both the thinning of layer 1 and the loss of synapses show a significant correlation with behavioral measures of memory function.
We first used conventional retrograde tracers to map the origin of thalamic projections to five prefrontal regions: medial area 9 (9m), lateral area 9 (9l), dorsal area 46 (46d), ventral area 46, and lateral area 12.
To understand the basic cellular mechanisms that underlie these actions of dopamine (DA), we have investigated the influence of DA on the cellular properties of layer 3 pyramidal cells in area 46 of the macaque monkey PFC. These results show, for the first time, that DA modulates the activity of layer 3 pyramidal neurons in area 46 of monkey dorsolateral PFC in vitro.
Recent studies with nonhuman primates have shown that lesions of the mid-dorsolateral prefrontal cortex, which extends from the lip of the dorsal bank of the sulcus principalis to the midline (i.e., dorsal area 46 and 9/46 and area 9), give rise to severe and long-lasting impairments on self-ordered and externally ordered tasks designed to tax executive processing within working memory, rather than short-term memory per se. The mid-dorsolateral prefrontal region receives visuospatial input from the posterior dorsolateral region (areas 8 and 6) and from the cortex within the middle part (sulcal area 46) and the caudal part (area 8) of the sulcus principalis.
Selection, but not maintenance, was associated with activation of prefrontal area 46 of the dorsal lateral prefrontal cortex.
METHODS: To test this hypothesis, we determined the density of dendritic spines, markers of excitatory inputs, on the basilar dendrites of Golgi-impregnated pyramidal neurons in the superficial and deep portions of layer 3 in the dorsolateral prefrontal cortex (area 46) and in layer 3 of the primary visual cortex (area 17) of 15 schizophrenic subjects, 15 normal control subjects, and 15 nonschizophrenic subjects with a psychiatric illness (referred to as psychiatric subjects). RESULTS: There was a significant effect of diagnosis on spine density only for deep layer 3 pyramidal neurons in area 46 (P = .006). In contrast, spine density on neurons in superficial layer 3 in area 46 (P = .09) or in area 17 (P = .08) did not significantly differ across the 3 subject groups. Furthermore, spine density on deep layer 3 neurons in area 46 did not significantly (P = .81) differ between psychiatric subjects treated with antipsychotic agents and normal controls.
A large sample of 19 young (4-11 years old) and 40 aged (20-32 years old) rhesus monkeys was tested using a delayed response procedure known to require the functional integrity of area 46 of the prefrontal cortex. Modern stereological methods were then used to estimate the total volume of area 46 and the volume of layer I in brains from 21 young and aged monkeys. These findings indicate that gross morphometric alterations affecting cortical volume are unlikely to account for age-related decline in the information processing capacities of area 46 in primates.
METHOD: Measurements were made of the density of GAT-1 -immunoreactive cartridges in layers 2-3a, 3b-4, and 6 of dorsolateral prefrontal cortex area 46 in 30 subjects with schizophrenia, each of whom was matched to one normal and one psychiatric comparison subject.
Injection of multiple tracers into physiologically mapped regions AL, ML and CL of the auditory belt cortex revealed that anterior belt cortex was reciprocally connected with the frontal pole (area 10), rostral principal sulcus (area 46) and ventral prefrontal regions (areas 12 and 45), whereas the caudal belt was mainly connected with the caudal principal sulcus (area 46) and frontal eye fields (area 8a).
We recorded from neurons in area 46 and the frontal eye field (FEF) while monkeys performed a memory-guided eye movement task. Many neurons in area 46 responded more when the monkey expected a larger reward. The mixture of neural signals representing spatial working memory and reward expectation appears to be a distinct feature of area 46..
After treatment, a stereologic method was used to assess neuronal and glial density and cortical thickness in prefrontal area 46.
These results support a functional segregation within the dorsolateral prefrontal cortex for WM: the dorsolateral prefrontal cortex (area 46/8A) is selectively involved in spatial WM, whereas the dorsomedial convexity (area 9/8B) is not critically engaged in either spatial or nonspatial working memory. Furthermore, the specific involvement of area 46/8A in spatial sequencing as well as in single-item storage WM tasks supports, in the nonhuman primate, an areal dissociation based on domain rather than on processing demand..
The mid-dorsolateral prefrontal area 46 has working memory functions for putting current cognitive processing into context and for updating relevant information on a trial-by-trial basis. The data were consistent with recently disclosed anatomical locations of area 46 and they further document its interindividual variations in brain-to-scalp relationship.
However, in the adjacent area 46, only 12% of the PV-IR terminals in the middle layers formed type I synapses.
While endothelial eNOS outlined blood vessels in the brain, brain-derived (neural) bNOS labelled three well-defined cell types in area 46 of the prefrontal cortex, viz. This arrangement is most characteristic in area 46 of the prefrontal cortex; areas 10 and 12 display similar features.
The present analysis showed that only a restricted portion of what had previously been labelled as area 46 in the monkey has the same characteristics as area 46 of the human brain; the remaining part of this monkey region has the characteristics of a portion of the middle frontal gyrus in the human brain that had previously been included as part of area 9.
Its distant connections are with area 4, the ventral portion of area 46, area 7b, and area POa in the intraparietal sulcus (IPS). Its other connections are with area 4, area 44, the ventral portion of area 46, area ProM, CMAr, and the supplementary motor area (SMA). Its distant connections are with area 44; the dorsal portion of area 8 and the ventral portion of area 46; as well as CMAr, SMA, and the supplementary sensory area.
Injections that included rostral and orbital prefrontal areas (10, 46 rostral, 12) labeled the rostral belt and parabelt most heavily, whereas injections including the caudal principal sulcus (area 46), periarcuate cortex (area 8a), and ventrolateral prefrontal cortex (area12vl) labeled the caudal belt and parabelt.
The effect of age on layer 1 of area 46 of prefrontal cortex was determined in the cerebral cortices of 15 rhesus monkeys, 13 of which had been behaviorally tested.
A group and subgroup analysis revealed similarly located activation in right middle frontal gyrus (Brodmann's area 46) in both spatial and nonspatial [ working memory-control] subtractions.
Activity in a portion of the middle frontal gyrus, corresponding to Brodmann area 46, bore a linear relation to response latency and may index the extent of mental search.
Activation in the right dentate nucleus and in the left frontal area 46 was reduced during verbal auditory and expressive language and enhanced during motor speech functions in the autism as compared to the control group. The thalamus showed group differences concordant with area 46 for expressive language.
The rCBF activation study showed a greater increase in rCBF in the right dorsolateral prefrontal cortex (Brodmann's area 46), left inferior frontal cortex (Brodmann's area 44/45), left thalamus, and bilateral cerebellar hemisphere during the paired association task as compared to the choice reaction task, which suggests a possible involvement of cerebello-thalamo-cortical circuit in the memory processing.
Quantitative cytometric analysis of area 46 was undertaken in brains from schizophrenic patients to determine whether there are morphologic changes underlying these cognitive deficits. A direct, three-dimensional counting method was used to determine cell density and cortical thickness in Nissl-stained sections of area 46. The neuropathology of area 46 in schizophrenia is similar in direction and magnitude to that previously described in area 9 (Selemon et al. Psychiatry 52:805-818), except for the abnormalities in layer II, which are specific to area 46.
Attention was associated with activity in two sites, the right middle frontal gyrus (Brodmann area 46) and the right inferior parietal lobule (Brodmann area 40).
In the aware mode prestriate and dorsolateral prefrontal cortices (area 46) are active.
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.
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.
area 46 of Brodmann) is involved in inhibition of unwanted reflexive saccades, prediction (predictive saccades) and spatial memory.
Evidence shows that the cerebellar output extends even to what has been characterized as the ultimate frontal planning area, the "prefrontal" cortex, area 46.
Among these are a breakdown in the integrity of myelin around axons, an overall reduction in the volume of white matter in the cerebral hemispheres, thinning of layer I in area 46 of prefrontal cortex, and decreases in the cell density in cortically projecting brain stem nuclei.
Signal modifications were regularly observed in the prefrontal cortex (Brodmann's area 46) during the serial subtraction of prime numbers, whereas the number listing task poorly activated the same areas.
Patients were divided into small groups, each with lesions affecting one of the following cortical areas: left or right frontal eye field (FEF), left or right prefrontal cortex (area 46 of Brodmann) (PFC), left supplementary eye field (SEF), left or right posterior parietal cortex (PPC) and right parieto-temporal cortex (PTC).
The connectional results showed prefrontal cortex in the location of the frontal eye fields (area 8) and dorsal area 46 projected in a columnar pattern to all cortical layers of area TPOc, to layer IV of TPOi, and in a columnar fashion, with a moderate increase in density in layer IV, to TPOr.
In order to pursue the hypothesis that the dorsolateral prefrontal cortex is a source of cognitive deficit in schizophrenia, we developed an easily administered pen-and-paper human analogue of a visuospatial working memory task that in non-human primates activates the neurons of Walker area 46 (Goldman-Rakic, 1987). These data suggest that schizophrenic patients have visuospatial working memory deficits that are sensitive to pen-and-paper versions of the tasks that activate the Walker area 46 in non-human primates.
area 46 lies on the dorsolateral convexity and is either partially or completely surrounded by area 9. The superior border of area 46 with adjacent cortex is also variable within the middle and superior frontal sulci, as is the inferior border within the upper wall of the inferior frontal sulcus.
Light microscopic analysis confirmed that the cortical layers are more differentiated in area 46 than in area 9, particularly at the borders of layer IV. Layers III and V exhibit clearer sublamination in area 9, while layer IV is also somewhat wider in area 46 than in area 9 (9.3% vs 6.4% of cortical thickness); the overall thickness of the cortex is the same in both areas. Cytometric analysis revealed that layer IV neurons of area 46 are more densely packed than those in area 9 (55.38 +/- 7.26 vs 45.80 +/- 4.45 neurons/0.001 mm3), as are neurons in the supragranular layers II and III combined (53.51 +/ 6.33 vs 45.69 +/ 3.81 neurons/0.001 mm3). Finally, neurons in area 46 are more homogeneous in size than those in area 9. Differences in myeloarchitecture are also evident: each area contains numerous, well-stained radial striae and two pronounced bands of horizontal fibers, but in general, area 46 is less myelinated than area 9.
In addition, in area 46, a region of prefrontal association cortex not known to be functionally lateralized, the mean somal size of the largest layer III pyramidal neurons was significantly (p < .001) smaller in the left hemisphere (402.4 +/- 84.9 microns2) than in the right (437.8 +/- 88.3 microns2).
The prefrontal cortex (area 46 of Brodmann) plays a crucial role for planning saccades to remembered target locations.
The frontal eye field (area 8a) was found to project to PMv and rPMd, and area 46 was labeled substantially only from rPMd.
Here, retrograde transneuronal transport of herpes simplex virus type 1 (HSV1) was used to identify subcortical neurons that project via the thalamus to area 46 of the primate prefrontal cortex. Many neurons in restricted regions of the dentate nucleus of the cerebellum and in the internal segment of the globus pallidus were labeled by transneuronal transport of virus from area 46.
Local injection of the alpha 2-adrenergic antagonist yohimbine (10 micrograms in 2 microliters saline) into the dorsolateral prefrontal cortex (Walker's area 46 and area 9) impaired the performance of the delayed-response task, and it was without effect on the performance of the task if there was no delay between the cue and choice signals.
The MR signal increased in an area of the middle frontal gyrus corresponding to Brodmann's area 46 in all eight subjects performing the spatial working memory task.
Then, in the same animal, we placed multiple injections of another retrograde tracer in and around the principal sulcus (Walker's area 46).
area 46 of Brodmann, control eye movements.
A strong input originates from area 46.
Two paradigms of memory-guided saccades were studied in 14 patients with focal vascular lesions affecting either the frontal eye field (FEF), or the supplementary eye field (SEF) or Brodmann's area 46 in the prefrontal cortex (PFC), and in 13 age-matched control subjects.
Parvalbumin-IR neurons are present in layers II-VI of the macaque principal sulcus (Walker's area 46) and are concentrated in a band centered around layer IV.
Although the frontal cortex of the baboon brain exhibits the same basic cytoarchitectural features as the frontal corticies of the cercopithecus (campbelli?) (Vogt and Vogt, '19) or the macaque (Walker, '40; Barbas and Pandya, '87, '89), the baboon frontal cortex is very different from that of the macaque and cercopithecus in terms of cytoarchitecture: (1) the baboon frontal cortex has an additional area, termed here "6a gamma", within area 6, which has cytoarchitectural characteristics that are intermediate between those of areas 6 and 8; (2) the aggregation of giant pyramidal cells (greater than 50 microns in diameter) is found only in area 4a in the baboon, whereas such aggregates are found in areas 4a and 4b and, occasionally, in area 4c in the macaque; and (3) area 46 of the prefrontal cortex of the baboon can be subdivided into the cortex that surrounds the principal sulcus (area 46) and the upper and lower banks of the principal sulcus (area 46ps).
Willed acts in the two response modalities studied (speaking a word, or lifting a finger) were associated with increased blood flow in the dorsolateral prefrontal cortex (Brodmann area 46).
Lesions affected (1) the superior part of the angular gyrus (area 39 of Brodmann) in the posterior parietal cortex (PPC), (2) the dorsolateral prefrontal cortex (PFC) (area 46 of Brodmann), (3) the frontal eye field (FEF), or (4) the supplementary motor area (SMA).
The lesions affected either (1) the posterior parietal cortex (PPC), (2) the dorsolateral frontal cortex (DLFC), involving the frontal eye field (FEF) and/or the prefrontal cortex (PFC) (area 46 of Brodmann), or (3) the supplementary motor area in the dorsomedial frontal cortex (DMFC).
Conversely, when subjects made lexical decisions about words that were heard, there was an increase in superior temporal activity with no change in area 46.
The basoventral regions injected with tracers included the orbital periallocortex and proisocortex, orbital areas 13, 11, and 12, lateral area 12, and ventral area 46.
The next stage of architectonic regions includes orbital areas 12, 11, and 14, which is followed by area 10, lateral area 12, and the rostral part of ventral area 46. The last group includes the caudal part of ventral area 46 and ventral area 8. The next stage includes lateral areas 10 and 9 and the rostral part of dorsal area 46. The last group includes the caudal part of dorsal area 46 and dorsal area 8.
dorsal area 46, areas 9 and 10, whereas the caudal segment of TPO has reciprocal connections with caudal subdivisions (areas 46, 8, and 6) of the lateral frontal lobe.
In addition, in the same material, the pattern of connections between the arcuate area and area 46 of the prefrontal cortex was studied. Anterogradely labeled axon terminals and retrogradely labeled cells appeared in the premotor area, in the supplementary motor area, and in area 46 on the side of injection; sites containing labeled axon terminals also contained labeled cells. In area 46 of the banks of the principal sulcus in the prefrontal cortex, labeled terminals were distributed in all cortical layers or over the entire cortical depth with a lower concentration in layer IV; labeled cells were found mostly in layers III and V, with a relatively high density in layer V..
The basoventral regions injected with tracers included basal (orbital) areas 11 and 12, lateral area 12, and ventral area 46. The rostral inferior temporal region was the predominant source of visual projections to orbital prefrontal sites, whereas lateral area 12 and ventral area 46 also received projections which were found more caudally.
For example, in the lightly innervated fundus of the principal sulcus (area 46), labeled fibers were primarily present in layer I and layers V-VI, whereas in area 9, the most densely innervated region, TH-labeled fibers were present in all cortical layers.
This paper reviews studies on that portion of the prefrontal cortex that is buried in and around the principal sulcus of macaque monkeys and corresponds to Brodmann's area 46 in man.
However, recent anatomical studies have elucidated the circuit basis for motor regulatory functions of the principal sulcus (Brodmann's area 9; Walker's area 46).
Area 24 (anterior cingulate) had the greatest density of immunoreactive cell bodies (148 +/- 14/mm2), area 9 was of intermediate density (109 +/- 13/mm2), and area 46 was the least dense (83 +/- 12/mm2).
Analysis of the thalamus in cases with fluorescent dye injections into the lateral orbital gyrus (Walker's area 11), principal sulcus (area 46), anterior bank of the arcuate gyrus (areas 8 and 45), supplementary motor area (area 6), and motor cortex (area 4) revealed topographic organization of the nigrothalamocortical projection system.
Horseradish peroxidase (HRP) histochemistry and double labeling with the fluorescent dyes nuclear yellow (NY) and fast blue (FB) were used to examine and compare the laminar and tangential arrangement of ipsilateral (associational) and contralateral (callosal) neurons and their relative density in three regions of prefrontal granular cortex: Walker's area 46 (principal sulcus), area 8A (superior limb of the arcuate sulcus), and area 11 (lateral orbital sulcus).
Following an HRP gel implant within the upper portion of the posterior (caudal) bank of the intraparietal sulcus, a prominent anterograde terminal projection field, consisting of alternate light and dark (300-500 microns) columns, was observed using low-power dark-field microscopy in the caudal third of the sulcus principalis cortex (area 46).
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