Brent A. Vogt

Connections of the Monkey Cingulate Cortex

Among several nineteenth century reports on the cortical convolution located above the corpus callosum, it was Burdach’s (1822) description that gave rise to the term cingulate gyrus. Early attempts to address the functional implications of the cingulate region were based primarily on limited neuro-anatomical observations and a host of gross comparative anatomical parallels. The most popular functional theory was formulated by Broca (1878), who suggested that the modality of olfaction was processed in a number of cerebral centers which included the anterior olfactory region, hippocampus, and cingulate gyrus. Collectively Broca termed these cerebral centers the grand lobe limbique. The cingulate gyrus was later shown to have extensive connections with the anterior thalamic nuclei (Clarke and Boggon, 1933).

Pain and Stroop interference tasks activate separate processing modules in anterior cingulate cortex

Abstract Investigations of pain using functional imaging techniques have revealed an extensive central network associated with nociception. This network includes the thalamus, insula, prefrontal cortex and anterior cingulate cortex (ACC) as well as the somatosensory cortices. Positron emission tomography (PET) of regional cerebral blood flow (rCBF) has demonstrated activation of the ACC during cognitively challenging tasks such as the Stroop interference task and divided attention. One interpretation of this research is that ACC is involved in the general features of attention and that it does not play a specific role in pain processing per se. Three-dimensional PET imaging provides a method for assessments of rCBF in a single individual during multiple tasks. In addition, coregistration of PET and magnetic resonance (MR) images allows for better localisation of the PET signals so that differences in cortical activation sites can be more accurately determined. This approach was used to assess rCBF during the experience of pain by subtracting images collected during heat from those during noxious heat stimulation. Two regions of the ACC had elevated rCBF, one in the perigenual region and one in the mid-rostrocaudal region (i.e. midcingulate cortex). During the execution of the Stroop task, the group result showed the midcingulate region overlapping with the site seen during the experience of pain. This group result, however, was not confirmed in the individual subject analysis, which revealed widespread and independent areas of ACC response to pain and Stroop. It is concluded that the ACC contributes to multiple cognitive procedures. It is inadequate to describe the primary contribution of ACC to pain processing as “attention” because it is unlikely that the multiple small and independent activation sites produced by pain and Stroop subserve attentive processing throughout the brain.

Atypical form of Alzheimer's disease with prominent posterior cortical atrophy: A review of lesion distribution and circuit disconnection in cortical visual pathways

In recent years, the existence of visual variants of Alzheimers disease characterized by atypical clinical presentation at onset has been increasingly recognized. In many of these cases post-mortem neuropathological assessment revealed that correlations could be established between clinical symptoms and the distribution of neurodegenerative lesions. We have analyzed a series of Alzheimers disease patients presenting with prominent visual symptomatology as a cardinal sign of the disease. In these cases, a shift in the distribution of pathological lesions was observed such that the primary visual areas and certain visual association areas within the occipito-parieto-temporal junction and posterior cingulate cortex had very high densities of lesions, whereas the prefrontal cortex had fewer lesions than usually observed in Alzheimers disease. Previous quantitative analyses have demonstrated that in Alzheimers disease, primary sensory and motor cortical areas are less damaged than the multimodal association areas of the frontal and temporal lobes, as indicated by the laminar and regional distribution patterns of neurofibrillary tangles and senile plaques. The distribution of pathological lesions in the cerebral cortex of Alzheimers disease cases with visual symptomatology revealed that specific visual association pathways were disrupted, whereas these particular connections are likely to be affected to a less severe degree in the more common form of Alzheimers disease. These data suggest that in some cases with visual variants of Alzheimers disease, the neurological symptomatology may be related to the loss of certain components of the cortical visual pathways, as reflected by the particular distribution of the neuropathological markers of the disease.

Anterior Cingulate Cortex and the Medial Pain System

The processing of sensory afferents in the cerebral cortex involves divergent processing of components of each sensory space. In the visual system, for example, there are separate and sequential, corticocortical projections for the analysis of form, color, movement, and depth (DeYoe and Van Essen, 1988; Livingstone and Hubel, 1988; Zeki and Shipp, 1988). A divergence of functional processing of different features of noci-ceptor-evoked activity may also occur in the cerebral cortex. Thus, there is a long history for dividing the pain system into two theoretical components: one involved in localization and sensory discrimination and the other involved in affective responses to noxious stimuli (e.g., Melzack and Casey, 1968; Melzack, 1975; Kenshalo and Willis, 1991).

Chapter 16 - The medial pain system, cingulate cortex, and parallel processing of nociceptive information

Nociceptive information in the cerebral cortex is thought to be processed according to discriminative properties, including localization and intensity, and affective associations. Stimulus localization is assessed mainly in somatosensory and posterior parietal cortices, while affective responses are processed in limbic regions. It has been known for four decades that ablations of anterior cingulated cortex (ACC) and its underlying white matter, the cingulum bundle, reduce or abolish affective responses to noxious stimuli, while sensory localization remains intact. Cingulate cortex forms a cingulum around the genual, dorsal, and splenial parts of the corpus callosum. The human cingulate sulci can form single or double parallel patterns that make averaging across cases difficult in functional imaging studies. The multiple sulcal patterns are related in turn to different depths with the single cingulated sulcus having the greatest depth of more than 1.5 cm. In order to expedite conversations about cingulate cortex, the cingulated gyrus is routinely divided into four regions that have unique cytoarchitectures, connections, and functions. The four regions and associated areas are as follows: perigenual areas 25, 24, and 32; midcingulate areas 24’ and 32’; posterior areas 23 and 31; retrosplenial areas 29 and 30. Since early distinctions between anterior and posterior cingulated cortices are not adequate for either structural or functional studies, the designation of a midcingulate region provides a simple regional designation to avoid such concepts as a posterior anterior cingulate cortex.

Tyrosinase mRNA is expressed in human substantia nigra

Dopamine acts, under appropriate conditions, as a selective neurotoxin. This toxicity is attributed to the autoxidation of the neurotransmitter into a reactive quinone that covalently modifies cellular macromolecules (i.e. proteins and nucleic acids). The oxidation of the catecholamine to a quinone is greatly accelerated by the enzyme tyrosinase. There is controversy, however, as to whether or not tyrosinase is expressed in human brain. In the present study, RT-PCR was utilized to demonstrate the presence of tyrosinase mRNA in post-mortem human brain tissues. Using gene-specific amplification primers, specific tyrosinase amplicons were detected following analysis of RNA from substantia nigra of four individuals. Analysis of cerebellar RNA from the same individuals produced no amplification products. Control reactions performed in the absence of reverse transcriptase failed to generate PCR products for any tissue tested. Three amplicons were subjected to direct DNA sequencing and all proved to be identical with tyrosinase sequences, thus obviating the possibility of amplification of a related gene. It is clear, therefore, that the tyrosinase gene is expressed in the human substantia nigra, lending support to previous studies describing tyrosinase-like activity and immunoreactive protein in the brain. This enzyme could be central to dopamine neurotoxicity as well as contribute to the neurodegeneration associated with Parkinsons disease.

Cytology of Human Caudomedial Cingulate, Retrosplenial, and Caudal Parahippocampal Cortices

Brodmann showed areas 26, 29, 30, 23, and 31 on the human posterior cingulate gyrus without marking sulcal areas. Histologic studies of retrosplenial areas 29 and 30 identify them on the ventral bank of the cingulate gyrus (CGv), whereas standardized atlases show area 30 on the surface of the caudomedial region. This study evaluates all areas on the CGv and caudomedial region with rigorous cytologic criteria in coronal and oblique sections Nissl stained or immunoreacted for neuron‐specific nuclear binding protein and nonphosphorylated neurofilament proteins (NFP‐ir). Ectosplenial area 26 has a granular layer with few large pyramidal neurons below. Lateral area 29 (29l) has a dense granular layer II‐IV and undifferentiated layers V and VI. Medial area 29 (29m) has a layer III of medium and NFP‐ir pyramids and a layer IV with some large, NFP‐ir pyramidal neurons that distinguish it from areas 29l, 30, and 27. Although area 29m is primarily on the CGv, a terminal branch can extend onto the caudomedial lobule. Area 30 is dysgranular with a variable thickness layer IV that is interrupted by large NFP‐ir neurons in layers IIIc and Va. Although area 30 does not appear on the surface of the caudomedial lobule, a terminal branch can form less that 1% of this gyrus. Area 23a is isocortex with a clear layer IV and large, NFP‐ir neurons in layers IIIc and Va. Area 23b is similar to area 23a but with a thicker layer IV, more large neurons in layer Va, and a higher density of NFP‐ir neurons in layer III. The caudomedial gyral surface is composed of areas 23a and 23b and a caudal extension of area 31. Although posterior area 27 and the parasubiculum are similar to rostral levels, posterior area 36′ differs from rostral area 36. Subregional flat maps show that retrosplenial cortex is on the CGv, most of the surface of caudomedial cortex is areas 23a, 23b, and 31, and the retrosplenial/parahippocampal border is at the ventral edge of the splenium. Thus, Brodmanns map understates the rostral extent of retrosplenial cortex, overstates its caudoventral extent, and abridges the caudomedial extent of area 23. J. Comp. Neurol. 438:353–376, 2001.

Localization of Mu and delta opioid receptors to anterior cingulate afferents and projection neurons and input/output model of Mu regulation.

Anterior cingulate cortex (ACC) has one of the highest densities of opioid receptors in the CNS and it has been implicated in acute and chronic pain responses. Little is known, however, about which neurons express opioid receptors in their dendrites and axon terminals. The present studies employed experimental techniques to remove afferent axons or classes of projection neurons from rat ACC area 24 followed by coverslip autoradiography to localize changes in binding of [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO) to mu receptors and 2-[3H]D-penicillamine-5-D-penicillamine-enkephalin (DPDPE) to delta receptors. Removal of all afferents to area 24 with undercut lesions did not alter DPDPE binding, but significantly reduced binding of DAMGO in layers I, III, and V. In contrast, removal of all cortical neurons with the excitotoxin ibotenic acid almost abolished DPDPE binding in all layers. The same lesions reduced DAMGO binding in most layers; however, there was a postlesion bimodal distribution in binding with high levels of binding in layer I and moderate levels in layer VI. These data suggest that delta receptors are expressed by cortical neurons, while mu receptors are expressed by both cortical neurons and afferent axons. To explore the distribution of postsynaptic receptors, immunotoxin lesions were made in area 24 by injection of OX7-saporin into the caudate and/or thalamic nuclei. Almost complete removal of projection neurons to these targets in layers Vb and VIa did not alter DPDPE binding, while the lesions reduced DAMGO binding in all but layer II. Removal of layer Vb corticostriatal projection neurons with caudate OX7-saporin injections reduced binding only in this layer. It is proposed that opioidergic circuits in area 24 are organized according to an input/output model for mu opioid regulation. In this model mu receptors regulate axon terminal activity from the thalamus in layer Ia and the locus coeruleus in layers Ic and II, whereas cortical outputs to the thalamus are modulated via postsynaptic receptors expressed in all layers by thalamocortical projection neurons with somata in layer VI. These opioidergic circuits in ACC are of particular importance because they may regulate responses to chronic nociceptive activity and associated pain perceptions.

Training-stage related neuronal plasticity in limbic thalamus and cingulate cortex during learning: a possible key to mnemonic retrieval.

This study is part of an ongoing project concerned with the analysis of the neural substrates of discriminative avoidance learning in rabbits. Multi-unit activity was recorded in 5 anterior and lateral thalamic nuclei and in 4 layers of 2 posterior cingulate cortical areas (29c/d and 29b) during learning. The rabbits learned to step in response to a warning tone to avoid a foot-shock, and to ignore a different tone not followed by shock. Excitatory training-induced unit activity (TIA, increased tone-elicited activity during training relative to a pretraining session with unpaired tone-shock presentations) and/or discriminative TIA (greater discharges to the warning than to the safe tone) developed during training in 11 of the 13 areas. Discriminative TIA in the thalamic nuclei increased monotonically as learning occurred. Anterodorsal (AD) thalamic excitatory TIA peaked in an early stage (the first session of training), laterodorsal thalamic and parvocellular anteroventral (AVp) excitatory TIA peaked in an intermediate stage (the session of the first behavioral discrimination), and magnocellular anteroventral (AVm) and anteromedial (AM) thalamic excitatory TIA peaked in a late stage (the session in which asymptotic behavioral discrimination first occurred). The excitatory TIA in these nuclei declined as training continued beyond the stage in which the peak occurred. Peaks of excitatory TIA developed in area 29c/d of posterior cingulate cortex in the early (layer IV), intermediate (layers I-III and V) and late (layer IV) training stages, as just defined. Only layer IV in area 29b of posterior cingulate cortex exhibited a peak of excitatory TIA, which occurred in the early and intermediate training stages. As in limbic thalamus, discriminative TIA increased monotonically over training stages in layers V and VI of areas 29c/d and in layer VI of area 29b. However, layers I-III and IV in area 29c exhibited peak discriminative TIA in the intermediate and late training stages, respectively. Lesion studies indicate that limbic thalamus and cingulate cortex are essential for learning. The peaks represent a unique topographic pattern of thalamic and cortical excitation elicited by the CS+. It is proposed that the peaks constitute a retrieval pattern, i.e. a unique topographic array of excitation. This pattern encodes the spatio-temporal context which defines the learning situation and is necessary for recall and output of the learned response.

NEUROFILAMENT AND CALCIUM-BINDING PROTEINS IN THE HUMAN CINGULATE CORTEX

Functional imaging studies of the human brain have suggested the involvement of the cingulate gyrus in a wide variety of affective, cognitive, motor, and sensory functions. These studies highlighted the need for detailed anatomic analyses to delineate its many cortical fields more clearly. In the present study, neurofilament protein, and the calcium‐binding proteins parvalbumin, calbindin, and calretinin were used as neurochemical markers to study the differences among areas and subareas in the distributions of particular cell types or neuropil staining patterns. The most rostral parts of the anterior cingulate cortex were marked by a lower density of neurofilament protein‐containing neurons, which were virtually restricted to layers V and VI. Immunoreactive layer III neurons, in contrast, were sparse in the anterior cingulate cortex, and reached maximal densities in the posterior cingulate cortex. These neurons were more prevalent in dorsal than in ventral portions of the gyrus. Parvalbumin‐immunoreactive neurons generally had the same distribution. Calbindin‐ and calretinin‐immunoreactive nonpyramidal neurons had a more uniform distribution along the gyrus. Calbindin‐immunoreactive pyramidal neurons were more abundant anteriorly than posteriorly, and a population of calretinin‐immunoreactive pyramidal‐like neurons in layer V was found largely in the most anterior and ventral portions of the gyrus. Neuropil labeling with parvalbumin and calbindin was most dense in layer III of the anterior cingulate cortex. In addition, parvalbumin‐immunoreactive axonal cartridges were most dense in layer V of area 24a. Calretinin immunoreactivity showed less regional specificity, with the exception of areas 29 and 30. These chemoarchitectonic features may represent cellular reflections of functional specializations in distinct domains of the cingulate cortex. J. Comp. Neurol. 384:597–620, 1997.