The cingulate bridge between allocortex, isocortex and thalamus.

The Fink-Heimer silver impregnation and the autoradiographic methods were used to study the fiber projections of the cingulate cortex in the squirrel monkey. It was found that this cortex provides inputs to the straitum, thalamus and several areas of isocortex. Evidence was found for a number of fiber projections (1) Fibers from the anterior limbic area were traced to the central part of the head of the caudate nucleus, putamen, septum, dorsomedial nucleus of the thalamus, anterior hypothalamus and lateral basal nucleus of the amygdala. (2) Projections from the cingulate area were traced to the lateral part of the head of the caudate nucleus, putamen, and to the centromedian, anterior, lateral dorsal, and lateral ventral thalamic nuclei and to medial nuclei of the base of the pons. (3) There were porjections from the retrosplenial area of the anterior, lateral dorsal, dorsomedial, and posterior thalamic nuclei and lateral nuclei of the pons. These results indicate that most of the cingulate gyrus is an intermediate structure between the thalamus and overlying cortex. The anterior limbic area forms a bridge between the thalamus and other areas of the cingulate gyrus and the frontal cortex. (4) the retrosplenial area and the posterior part of the cingulate area bridge the adjacent visual snesory association cortex and pelvic areas of the snesory motor cortex, respectively. These areas of the cingulate gyrus project directly to the striatum as well as to the thalamus, structurally providing limbic system input to subcortical motor structures.     

Local norepinephrine depletion and learning-related neuronal activity in cingulate cortex and anterior thalamus of rabbits

Summary Multi-unit neuronal activity was recorded in posterior cingulate cortex (area 29) and the anterior ventral (AV) thalamic nucleus during discriminative instrumental avoidance learning wherein a response (stepping in an activity wheel) to a 0.5-s tone (CS⁺) prevented a foot-shock 5 s after CS⁺ onset. Presentations of a different tone (CS^-) on 50% of the conditioning trials in an irregular sequence with the CS⁺ did not predict shock and thus required no response. Two groups of rabbits received intracranial micro-injections of 6-hydroxydopamine (6-OHDA) to locally deplete the NE in area 29 or the AV nucleus. Vehicle was injected in the non-depleted area in each group and a third group received vehicle injections in both areas. Dopamine neurons in subjects that received 6-OHDA were protected by pre-treatment with GBR-12909. Neuronal data were collected during two pre-training sessions in response to the tones only and when the tones and shock were presented unpaired. Thalamically depleted rabbits made more, and cortically depleted rabbits made fewer, avoidance responses than controls during the early stages of behavioral acquisition, and cortically depleted rabbits made fewer responses than controls and thalamically depleted rabbits during extinction testing administered after the completion of acquisition. One effect of NE depletion on neuronal activity was entirely local: elimination of neuronal sensitization effects (enhanced discharges elicited by tones during the unpaired tone-shock pre-training treatment relative to pre-training with tones only). Other neuronal effects of NE depletion were system-wide, i.e., they occurred whether the depletion was cortical or thalamic. These were: attenuation of area 29 tone-elicited neuronal discharges and enhancement of AV thalamic discharges before and during training; elimination in area 29 of neuronal discrimination between CS⁺ and CS^-, induced in controls by CS⁺-shock pairings in the first conditioning session; induction of this neuronal discrimination, not present in controls, in the AV nucleus during the first conditioning session; attenuation of discharge enhancements elicited in controls by unexpected stimuli (presentation of auditory stimuli different in quality and incidence from the CS⁺). Excepting the noted losses at the outset of training, the results did not support an involvement of NE in the production of cingulate cortical or AV thalamic excitatory and discriminative training-induced neuronal activity. The system-wide alterations due to NE depletion implicated NE in the processing of unexpected events and in the production of dynamic neuronal patterns relevant to mnemonic retrieval. Several of the depletion-related neuronal changes were similar to the effects of hippocampal formation (subicular) lesions, suggesting that NE-dependent functions in area 29 and the AV nucleus are governed by hippocampal efferents, which may control the release of NE in these areas.     

The relationship between reaction time, error rate and anterior cingulate cortex activity.

Current concepts of cognitive control suggest that the anterior cingulate cortex (ACC) is involved in performance monitoring. This idea is supported by the finding that increased ACC activity is found in situations in which errors are likely to occur, even if none are actually made. In addition, recent results suggest that increased ACC activity is negatively correlated with reaction time. We have now compared the error rates and the ACC activity of healthy subjects with short (n=19) vs. long reaction times (n=17) in an auditory choice reaction paradigm and analysed the current density differences in the ACC in the time range of the N1 component with low resolution electromagnetic tomography. Subjects with short reaction times showed significantly more ACC activation (Brodmann Area 24) and an increased error rate. This finding suggests that increased ACC activity is associated with a gain in reaction speed at the expense of correctness and is discussed in the context of current concepts about the role of the ACC in cognitive functions.     

Neuronal encoding of conditional stimulus duration in the cingulate cortex and the limbic thalamus of rabbits

Neuronal activity in cingulate cortex was recorded during discriminative active avoidance conditioning of rabbits. In one subpopulation of neurons, brief (200 and 500 ms) conditional stimuli (CSs) elicited greater average cingulate cortical training-induced neuronal discharges during conditioned response acquisition than did a long (5,000 ms) CS, and the amount of neuronal discrimination between CS+ and CS- was greater in response to the brief CSs than to the long CS. Neurons in a different subpopulation did not encode CS duration per se but were sensitive to the novelty of the CS duration. Medial dorsal and anteroventral thalamic neurons were suppressed by novel CS durations that activated novelty-sensitive neurons in related cingulate cortical areas. These results are discussed in relation to a theoretical model of the neural mediation of avoidance conditioning.     

Combined lesions of septum,amygdala, hippocampus,anterior thalamus,mamillary bodies and cingulate and subicular cortex fail to impair the acquisition of complex learning tasks

Summary Previous investigations (Irle and Markowitsch 1982a, 1983, 1984) demonstrated that triple or fourfold lesions within the cat's limbic system fail to produce learning impairments, as opposed to lesions of single or double loci, when tasks of visual reversal, delayed alternation, and active two-way avoidance were used. On the basis of these results, limbic regions of the cat's brain might be considered unessential for intact learning and mnemonic functions. Therefore, in order to obtain indisputable information on the importance of the limbic system for learning and memory, lesions of nearly all limbic core regions of the cat were performed. Ten cats received lesions of seven limbic core regions: the septum, amygdala, anterior thalamus, mamillary bodies, cingulate cortex, subicular cortex, and the hippocampus proper. Nine of these animals were tested postoperatively in the acquisition of a visual reversal task, a spatial alternation and delayed alternation task, and an active two-way avoidance task, and were then compared to the performance levels of ten control animals. The experimental animals turned out to be unimpaired in all tasks tested; the performance scores in the visual reversal and delayed alternation task and — for some experimental animals in the active two-way avoidance task even indicate a slight, though statistically insignificant, facilitation in the learning behavior of these animals. It is assumed that the learning functions underlying the tasks used were taken over by other brain regions, which, prior to massive limbic lesions, may be suppressed or otherwise inhibited. Alternatively, utilization of spared tissue in the damaged limbic regions must be considered as the possible explanation.     

Intracortical circuits in rat anterior cingulate cortex are activated by nociceptive inputs mediated by medial thalamus

We investigated the afferents and intracortical synaptic organization of the anterior cingulate cortex (ACC) during noxious electrical stimulation. Extracellular field potentials were recorded simultaneously from 16 electrodes spanning all layers of the ACC in male Sprague-Dawley rats anesthetized by halothane inhalation. Laminar-specific transmembrane currents were calculated with the current source density analysis method. Two major groups of evoked sink currents were identified: an early group (latency = 54.04 +/- 2.12 ms; 0.63 +/- 0.07 mV/mm(2)) in layers V-VI and a more intense late group (latency = 80.07 +/- 4.85 ms; 2.16 +/- 0.22 mV/mm(2)) in layer II/III and layer V. Multiunit activities were evoked mainly in layer V and deep layer II/III with latencies similar to that of the early and late sink groups. The evoked EPSP latencies of pyramidal neurons in layers II/III and V related closely with the sink currents. The sink currents were inhibited by intracortical injection of CNQX (1 mM, 1 microl), a glutaminergic receptor antagonist, and enhanced by intraperitoneal (5 mg/kg) and intracortical (10 microg/microl, 1 microl) injection of morphine, a mu-opioid receptor agonist. Paired-pulse depression was observed with interpulse intervals of 50 to 1,000 ms. High-frequency stimulation (100 Hz, 11 pulses) enhanced evoked responses in the ACC and evoked medial thalamic (MT) unit activities. MT lesions blocked evoked responses in the ACC. Our results demonstrated that two distinct synaptic circuits in the ACC were activated by noxious stimuli and that the MT is the major thalamic relay that transmits nociceptive information to the ACC.     

Interconnections between the pretectum and visual thalamus in reptiles, Caiman crocodilus.

Interconnections between the visual thalamus and the pretectum were investigated in one species of reptiles, Caiman crocodilus, by injections of horseradish peroxidase into nucleus rotundus. Nucleus pretectalis was identified as a major target of rotundal efferents as well as a significant input to nucleus rotundus. The presence of a pretectal nucleus with neural connections and topographic location similar to nucleus pretectalis of Caiman has been described in lizards and pigeons. Taken together, these observations suggest that this pretectal nuclear group and its associated fiber path may be a feature common to all non-mammalian amniotes.     

Intrinsic functional relations between human cerebral cortex and thalamus

The brain is active even in the absence of explicit stimuli or overt responses. This activity is highly correlated within specific networks of the cerebral cortex when assessed with resting-state functional magnetic resonance imaging (fMRI) blood oxygen level–dependent (BOLD) imaging. The role of the thalamus in this intrinsic activity is unknown despite its critical role in the function of the cerebral cortex. Here we mapped correlations in resting-state activity between the human thalamus and the cerebral cortex in adult humans using fMRI BOLD imaging. Based on this functional measure of intrinsic brain activity we partitioned the thalamus into nuclear groups that correspond well with postmortem human histology and connectional anatomy inferred from nonhuman primates. This structure/function correspondence in resting-state activity was strongest between each cerebral hemisphere and its ipsilateral thalamus. However, each hemisphere was also strongly correlated with the contralateral thalamus, a pattern that is not attributable to known thalamocortical monosynaptic connections. These results extend our understanding of the intrinsic network organization of the human brain to the thalamus and highlight the potential of resting-state fMRI BOLD imaging to elucidate thalamocortical relationships.     

The distribution of plasma proteins in the neocortex and early allocortex of the developing sheep brain

Summary The histogenesis of the cerebral neocortex and early allocortex of the sheep has been described and, using an immunohistochemical technique, five plasma proteins have been identified in the telencephalic wall and their distribution followed during its differentiation. The development of the neocortex was studied from 18 days gestation, when the neural tube was still open, to 120 days, when the adult structure was established. A primordial plexiform layer was formed above the ventricular zone by 25 days and by 35 days this layer was divided by the differentiating cortical plate into an outer marginal zone and an inner subplate zone. The appearance of the subventricular and intermediate zones by 50 days gestation completed the formation of the neocortical layers. The differentiation of the allocortex was generally less advanced than the neocortex up to 40 days gestation, when the primordium of the pyramidal layer was beginning to develop.The five plasma proteins identified, fetuin, -fetoprotein, albumin, transferrin and ₁-antitrypsin, are quantitatively the most important in the csf and plasma of the sheep fetus. Fetuin was the earliest plasma protein to be detected in the brain and it was also the most widespread; positive staining for this protein was seen in cells and fibres of all layers as they differentiated and could still be identified in some mature neurons at 120 days. -Fetoprotein and albumin had a limited distribution, appearing in cells in the developing cortical plate for a short period early in gestation (35–40 days), but mainly confined to the ventricular zones later and barely detectable by 80 days gestation. Transferrin appeared to have a different distribution, being detected in fibres first in the primordial plexiform layer and then in the marginal and subplate zones, only later being identified in cells of the cortical plate. From their distribution it is suggested that fetuin and transferrin may play an important role in the differentiation of the cortex and the establishment of correct connections between fiber systems and migrating cells at certain stages of development. ₁-Antitrypsin was only found in a few cells during a restricted period of gestation. All five plasma proteins were identified in precipitated csf and plasma at most ages examined, although at 18 days gestation albumin, transferrin and ₁-antitrypsin and at 120 days, -fetoprotein, could not be detected. The pattern of distribution of plasma proteins in the telencephalic wall suggests that they could originate either by uptake from csf and subsequent migration of protein containing cells or by local synthesis within some cells during a limited period of differentiation.     

The anterior cingulate and reward-guided selection of actions

Macaques were taught a reward-conditional response selection task; they learned to associate each of two different actions to each of two different rewards and to select actions that were appropriate for particular rewards. They were also taught a visual discrimination learning task. Cingulate lesions significantly impaired selection of responses associated with different rewards but did not interfere with visual discrimination learning or performance. The results suggest that 1) the cingulate cortex is concerned with action reward associations and not limited to just detecting when actions lead to errors and 2) that the cingulate cortex's function is limited to action reinforcer associations and it is not concerned with stimulus reward associations.     

Correlation between alerting rhythm and unit activity in the rabbit thalamus

The alerting rhythm, regular electroencephalographic (EEG) waves with a frequency of 4–10/sec arising simultaneously in several structures of the rabbit's brain, is seen during orienting, defensive and food-seeking behavior (1, 2, 4, 6, 7, 9). Questions of interest have to do with the topography of its spread through different brain structures and with the location of structures in which it is actually generated. In the light of these questions, a search for neurons whose activity determines the genesis of the alerting rhythm is of great importance.In these experiments with unanesthetized rabbits the connection between thalamic unit activity and the alerting rhythm arising as a component of the orienting reflex to sensory stimulation was investigated. No comparable data was found in the literature.     

The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome

The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post‐mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p < 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = −0.58, p = 0.009) and age of death (Spearman r = −0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS.     

The distribution of calbindin, calretinin and parvalbumin immunoreactivity in the human thalamus

Calcium-binding proteins show a heterogeneous distribution in the mammalian central nervous system and are useful markers for identifying neuronal populations. The distribution of the three major calcium-binding proteins - calbindin-D28k (calbindin), calretinin and parvalbumin - has been investigated in eight neurologically normal human thalami using standard immunohistochemical techniques. Most thalamic nuclei show immunoreactive cell bodies for at least two of the three calcium-binding proteins; the only nucleus showing immunoreactivity for one calcium-binding protein is the centre médian nucleus (CM) which is parvalbumin-positive. Overall, the calcium-binding proteins show a complementary staining pattern in the human thalamus. In general terms, the highest density of parvalbumin staining is in the component nuclei of the ventral nuclear group (i.e. in the ventral anterior, ventral lateral and ventral posterior nuclear complexes) and in the medial and lateral geniculate nuclear groups. Moderate densities of parvalbumin staining are also present in regions of the mediodorsal nucleus (MD). By contrast, calbindin and calretinin immunoreactivity both show a similar distribution of dense staining in the thalamus which appears to complement the pattern of intense parvalbumin staining. That is, calbindin and calretinin staining is most dense in the rostral intralaminar nuclear group and in the patchy regions of the MD which show very low levels of parvalbumin staining. However, calbindin and calretinin also show low levels of staining in the ventral nuclear complex and in the medial and lateral geniculate bodies which overlaps with the intense parvalbumin staining in these regions. These results show that the calcium-binding proteins are heterogeneously distributed in a complementary fashion within the nuclei of the human thalamus. They provide further support for the concept recently proposed by Jones (Jones, E.G., 1998. Viewpoint: the core and matrix of thalamic organization. Neuroscience 85, 331-345) that the primate thalamus comprises of a matrix of calbindin immunoreactive cells and a superimposed core of parvalbumin immunoreactive cells which may have differential patterns of cortical projections.     

Choice, uncertainty and value in prefrontal and cingulate cortex

Reinforcement learning models that focus on the striatum and dopamine can predict the choices of animals and people. Representations of reward expectation and of reward prediction errors that are pertinent to decision making, however, are not confined to these regions but are also found in prefrontal and cingulate cortex. Moreover, decisions are not guided solely by the magnitude of the reward that is expected. Uncertainty in the estimate of the reward expectation, the value of information that might be gained by taking a course of action and the cost of an action all influence the manner in which decisions are made through prefrontal and cingulate cortex.     

A double dissociation between mood states and personality traits in the anterior cingulate

Neuroticism and extraversion are personality traits associated with negative and positive mood states, respectively, confounding trait and state factors that may affect brain responses to emotional stimuli. The authors dissociated these factors using fMRI and the emotional Stroop attention task: Anterior cingulate (AC) response to positive stimuli varied as a function of personality trait, but not mood state, whereas AC response to negative stimuli varied as a function of mood state, but not personality trait. Negative mood, but not personality trait, also increased the functional connectivity between AC and other regions. Variance in AC activation can thus be ascribed to an intersubject variable (extraversion) when responding to positive stimuli and an intrasubject variable (mood) when responding to negative stimuli. The former may explain stable differences between extraverts and introverts. The latter may provide an adaptive mechanism to expand an individual's dynamic range in response to potentially dangerous or threatening stimuli.     

Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging

Evidence concerning anatomical connectivities in the human brain is sparse and based largely on limited post-mortem observations. Diffusion tensor imaging has previously been used to define large white-matter tracts in the living human brain, but this technique has had limited success in tracing pathways into gray matter. Here we identified specific connections between human thalamus and cortex using a novel probabilistic tractography algorithm with diffusion imaging data. Classification of thalamic gray matter based on cortical connectivity patterns revealed distinct subregions whose locations correspond to nuclei described previously in histological studies. The connections that we found between thalamus and cortex were similar to those reported for non-human primates and were reproducible between individuals. Our results provide the first quantitative demonstration of reliable inference of anatomical connectivity between human gray matter structures using diffusion data and the first connectivity-based segmentation of gray matter.