Grasping behavior in schizophrenia suggests selective impairment in the dorsal visual pathway.

This study frames anomalous functional brain organization in schizophrenia (SCZ) within an evolutionary model of brain development, the dual trends theory (DTT). The DTT argues that neural architecture develops along 2 separate pathways: the dorsal archicortical trend and the ventral paleocortical trend. The DTT dovetails with visual system organization, which is also composed of 2 independent pathways: a dorsal stream dedicated to visuomotor action and a ventral stream dedicated to perceptual processing. The present study examined the integrity of these pathways using a size-contrast visual illusion. Prior research has shown that, normally, perceptual estimations of object size are susceptible to visual illusions, whereas goal-directed actions are resistant. The authors hypothesized that, unlike control participants, SCZ patients' actions would be susceptible to the illusion, reflecting dorsal stream dysfunction. Here, 42 SCZ patients and 42 healthy controls grasped and estimated the size of target blocks in control and illusion conditions. During estimation, both groups were equally perturbed by the illusion; however, grasping movements of patients alone were influenced by the illusion. These results suggest disrupted dorsal brain circuitry in SCZ but relatively intact ventral circuitry. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Membrane-associated molecules guide limbic and nonlimbic thalamocortical projections

Membrane-associated signals expressed in restricted domains of the developing cerebral cortex may mediate axon target recognition during the establishment of thalamocortical projections, which form in a highly precise manner during development. To test this hypothesis, we first analyzed the outgrowth of thalamic explants from limbic and nonlimbic nuclei on membrane substrates prepared from limbic cortex and neocortex. The results show that different thalamic fiber populations are able to discriminate between membrane substrates prepared from target and nontarget cortical regions. A candidate molecule that could mediate selective choice in the thalamocortical system is the limbic system-associated membrane protein (LAMP), which is an early marker of cortical and subcortical limbic regions (Pimenta et al.,1995) that can promote outgrowth of limbic axons. Limbic thalamic and cortical axons showed preferences for recombinant LAMP (rLAMP) in a stripe assay. Incubation of cortical membranes with an antibody against LAMP prevented the ability of limbic thalamic fibers to distinguish between membranes from limbic cortex and neocortex. Strikingly, nonlimbic thalamic fibers also responded to LAMP, but in contrast to limbic thalamic fibers, rLAMP inhibited branch formation and acted as a repulsive axonal guidance signal for nonlimbic thalamic axons. The present studies indicate that LAMP fulfills a role as a selective guidance cue in the developing thalamocortical system.     

Physician awareness of prescription drug costs: a missing element of drug advertising and promotion

The effects of high-dose ketamine on the c-fos protein (c-Fos) expression were investigated in rat by an immunohistochemical technique. The administration of 100 mg/kg ketamine i.p. induced seizure-like activity (limbic seizure). No c-Fos immunoreactivity was observed in hippocampus, piriform cortex and amygdala, while it was observed in neocortex and thalamus. These findings disagree with the reports that ketamine depresses the neuronal function of the neocortex and thalamus, while it stimulates the limbic system.     

A role for the bilateral involvement of perirhinal cortex in generalized kindled seizure expression

The perirhinal cortex (PRh) has been suggested as a substrate for the expression of generalized clonic seizures in the late stages of kindling development (stages 4-5). Using the induction of Fos as a marker of neuronal activation, the PRh region was investigated after kindling or nonkindling electrical stimulation. Nonkindling electrical stimulation of the PRh elicited stimulus-locked behaviors, without afterdischarge. These behaviors were characterized by rearing and bilateral forelimb clonus which were terminated upon electrical stimulus offset in half of the rats displaying this behavior (with the other half expressing self-sustained seizures). In these animals, Fos immunoreactivity was found throughout neocortical and subcortical structures in the hemisphere ipsilateral to the stimulating electrode. By contrast, Fos-immunoreactivity in the contralateral hemisphere was localized primarily in the PRh and frontal motor cortex. Likewise, similar patterns of Fos immunoreactivity were observed in both hemispheres of rats following kindling to one generalized clonic seizure from several limbic and paleocortical structures. These results suggest that the bilateral involvement of the PRh is critical in producing the bilateral behaviors associated with generalized clonic seizure expression. In support of this interpretation, infusion of 3 M KCl directly into the contralateral PRh of rats kindled to a single stage 4-5 (generalized clonic) seizure from the ipsilateral amygdala reduced seizure manifestations from a generalized clonic seizure (stage 4-5) to a unilateral clonic seizure (stage 3) without affecting measures of focal excitability. Taken together, these data indicate a role for the bilateral involvement of the PRh in generalized clonic seizure expression whether evoked from the naive or kindled state. These results further indicate that bilateral behaviors require the bilateral involvement of the structures necessary for the expression of these behaviors.     

The psychophysiological criteria for assessing the excitable type of psychopathy

In the excitable psychopaths and persons with some psychopathic traits (Leonard's "accentuated personality") the study was made of a cognitive function of discriminating microintervals and event-related potentials to visual stimuli. A qualitative difference in the accomplishment of the cognitive task between the two groups was found. Disturbances of the cognitive function, learning deficiency and reduction of the P300 wave provide grounds for referring this "antisocial personality disorder" to pathology of the limbic system of the brain.     

Regional changes in forebrain activation during the early and late phase of formalin nociception: analysis using cerebral blood flow in the rat

This is the first neural imaging study to use regional cerebral blood flow (rCBF) in an animal model to identify the patterns of forebrain nociceptive processing that occur during the early and late phase of the formalin test. We measured normalized rCBF increases by an autoradiographic method using the radiotracer [99mTc]exametazime. Noxious formalin consistently produced detectable, well-localized and typically bilateral increases in rCBF within multiple forebrain structures, as well as the interpeduncular nucleus (Activation Index, AI = 66) and the midbrain periaqueductal gray (AI = 20). Structures showing pain-induced changes in rCBF included several forebrain regions considered part of the limbic system. The hindlimb region of somatosensory cortex was significantly activated (AI = 31), and blood flow increases in VPL (AI = 8.7) and the medial thalamus (AI = 9.0) exhibited a tendency to be greater in the late phase as compared to the early phase of the formalin test. The spatial pattern and intensity of activation varied as a function of the time following the noxious formalin stimulus. The results highlight the important role of the limbic forebrain in the neural mechanisms of prolonged persistent pain and provide evidence for a forebrain network for pain.     

Disconnection of the anterior cingulate cortex and nucleus accumbens core impairs Pavlovian approach behavior: Further evidence for limbic cortical–ventral striatopallidal systems.

The nucleus accumbens (NAcc) has been implicated in a variety of forms of reward-related learning, reflecting its anatomical connections with limbic cortical structures. After confirming that excitotoxic lesions of the anterior cingulate cortex (Ant Cing) impaired the acquisition of appetitive Pavlovian conditioning in an autoshaping procedure, the effects of excitotoxic lesions to the NAcc core or shell on autoshaping were also assessed. Only selective core lesions impaired Pavlovian approach. A subsequent experiment studied the effects of a disconnection of the Ant Cing and NAcc core, using an asymmetric lesion procedure, to determine whether these structures interact sequentially as part of a limbic corticostriatal system. Such lesioned rats were also significantly impaired relative to controls at autoshaping. These results demonstrate that the NAcc core and Ant Cing are "nodes" of a corticostriatal circuit involved in stimulus-reward learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioural evaluation of cholinergic drugs

Alzheimer's disease involves progressive degeneration of the cortex and the limbic system. Loss of afferent forebrain neurochemical modulatory systems is also seen, most significantly of the basal forebrain cholinergic system. Drug discovery programmes have pursued enhancement of forebrain muscarinic function as a therapeutic target. The most promising muscarinic agonists described achieve functional selectivity as agonists as the M1/M3 receptors in the CNS and M2 antagonists. These compounds have fewer cardiac and other cholinergic side effects. In rodent and monkey models of reference and working memory, these compounds reverse the cognitive impairment induced with plopolamine. Acetylcholinesterase inhibitors are even more efficacious in these models.     

The biological affects: A typology.

This typology of biological affects is based on developmental-interactionist theory of motivation, emotion, and cognition. Affects—subjectively experienced feelings and desires—involve interoceptive perceptual systems based on primordial molecules that characterize neurochemicals. Biological affects involve primary motivational–emotional systems (primes) associated with hierarchically organized neurochemical systems in the brain, including subcortical (reptilian) and paleocortical (limbic) brain structures. Affects fulfill individualistic (selfish) functions (arousal, approach–avoidance, agonistic) and prosocial (cooperative) functions. Selfish and cooperative functions are associated respectively with the right and left hemispheres. Biological affects constitute the physiological bases for higher level affects: social affects (e.g., pride, guilt, shame, pity, jealousy), cognitive affects (e.g., curiosity, surprise), and moral affects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sensitivity to ageing of the limbic dopaminergic system: a review

The limbic system includes the complex of brain centres, nuclei and connections that provide the anatomical substrate for emotions. Although the presence of small amounts of dopamine (DA) in several limbic structures has been recognized for a long time, for many years it was thought that limbic DA represented a precursor of noradrenaline in the biosynthetic pathway of catecholamines. More recent evidence has shown that limbic centres and nuclei are supplied with a dopaminergic innervation arising from the ventral tegmental area (field A10) and in smaller amounts from the mesencephalic A9 field. The dopaminergic limbic system is sensitive to ageing. Parameters of dopaminergic neurotransmission (DA levels, biosynthetic and catabolic markers and DA receptors) undergo age-related changes which depend on the structure and species investigated and are characterized mainly by a decline of different parameters examined. In this paper, the influence of ageing on DA biosynthesis, levels, metabolism and receptors are reviewed in laboratory rodents, monkeys and humans as well as in cases of Alzheimer's disease and Parkinson's disease. The possibility that changes of dopaminergic neurotransmission markers in the limbic system are associated with cognitive impairment and psychotic symptoms affecting the elderly is discussed. Better knowledge of dopaminergic neurotransmission mechanisms in the so-called physiological ageing and in senile dementia may provide new insights in the treatment of behavioural alterations frequently occurring in old age.     

The organization of the cortical projection system of the putamen in dogs

Organization of cortical projections in dorsal and ventral segments of putamen rostral and caudal regions was studied in dogs using retrograde axonal transport of horse radish peroxidase. Dorsal region was shown to receive projections from neo- and mesocortex, while ventral is linked with all cortical units: neo-, meso- and allocortex. Dorsal part of putamen is to greater extent connected with cortical fields, relating to motor aspects of behavior (motor, premotor and somatosensory). Ventral region basically receives projections from the so called limbic cortical fields (cingular, insulary, orbital, periamygdalary and perirhinal). However, results of the present study do not allow to conclude on absolute division of projections of functionally different systems and only indicate the prevalence of one of them in certain topographic zone of the structure studied, i.e. elements of distinctive topography. consisting in presence of dorsal motor and ventral limbic morpho-functional regions are characteristic for dog putamen. No diversities in distribution of cortical projectional fibres along rostrocaudal axis of the structure were revealed. Initial neurons, projecting in putamen are of multilaminary localisation in the cortex.     

Increased benzodiazepine receptor density in the prefrontal cortex in patients with panic disorder

There are published studies concerning a regionally changed function of GABA-benzodiazepine-receptor-complexes in anxiety disorder. These studies implicate the limbic lobe, the brainstem and the prefrontal cortex. Using 123I-Iomazenil and single photon emission tomography (SPET) we investigated the benzodiazepine receptor density in twelve patients with panic disorder who had never been treated with benzodiazepines before. Nine age- and sex-matched volunteers who were free of mental illness served as controls. Patients with panic disorder showed a significant increase of benzodiazepine receptor binding in the right supraorbital cortex and a trend to an increased uptake in the right temporal cortex. There was no correlation between receptor density and scores on Spielberger's State Trait Anxiety Inventory in the patient group. Since the findings cannot be explained by benzodiazepine exposure we hypothesize an upregulation due to functional or neuroanatomic changes (at least) in the frontotemporal cortex.     

Aromatase in axonal processes of early postnatal hypothalamic and limbic areas including the cingulate cortex

It has been shown that sexual dimorphic morphology of certain hypothalamic and limbic areas underlie gender-specific sexual behavior and neuroendocrine mechanisms. The key role played by locally formed estrogen in these developmental events has been revealed during a critical perinatal period. In this study, we aimed to document the presence of estrogen-synthetase (aromatase)-immunoreactive elements in the involved limbic system and hypothalamus of the developing rat brain. On postnatal day 5, animals of both sexes were perfusion-fixed, and sections from the forebrain and hypothalamus were immunolabelled for aromatase using an antiserum that was generated against a 20 amino acid sequence of placental aromatase. Aromatase-immunoreactivity was present in neuronal perikarya and axonal processes in the following limbic structures: the central and medial nuclei of the amygdala, stria terminalis, bed nucleus of the stria terminalis (BNST), lateral septum, medial septum, diagonal band of Broca, lateral habenula and all areas of the limbic (cingulate) cortex. In the hypothalamus, the most robust labelling was observed in the medial preoptic area, periventricular regions, ventromedial and arcuate nuclei. The most striking feature of the immunostaining with this antiserum was its intracellular distribution. In contrast to the heavy perikaryal labelling that can be observed with most of the currently available aromatase antisera, in the present experiments, immunoperoxidase was predominantly localized to axons and axon terminals. All the regions with fiber staining corresponded to the projection fields of neuron populations that have previously been found to express perikaryal aromatase. Our results confirm the presence of aromatase-immunoreactivity in developing limbic and hypothalamic areas. The massive expression of aromatase in axonal processes raises the possibility that estrogen formed locally by aromatase may not only regulate the growth, pathfinding and target recognition of its host neuronal processes, but may also exert paracrine actions on structures in close proximity, including the target cells.     

Pain affect encoded in human anterior cingulate but not somatosensory cortex

Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious stimuli, without changing the perceived intensity. Positron emission tomography revealed significant changes in pain-evoked activity within anterior cingulate cortex, consistent with the encoding of perceived unpleasantness, whereas primary somatosensory cortex activation was unaltered. These findings provide direct experimental evidence in humans linking frontal-lobe limbic activity with pain affect, as originally suggested by early clinical lesion studies.     

Neuropsychological correlates of early symptoms of autism

Both the medial temporal lobe and dorsolateral prefrontal cortex have been implicated in autism. In the present study, performance on two neuropsychological tasks--one tapping the medial temporal lobe and related limbic structures, and another tapping the dorsolateral prefrontal cortex--was examined in relation to performance on tasks assessing autistic symptoms in young children with autism, and developmentally matched groups of children with Down syndrome or typical development. Autistic symptoms included orienting to social stimuli, immediate and deferred motor imitation, shared attention, responses to emotional stimuli, and symbolic play. Compared with children with Down syndrome and typically developing children, children with autism performed significantly worse on both the medial temporal lobe and dorsolateral prefrontal tasks, and on tasks assessing symptoms domains. For children with autism, the severity of autistic symptoms was strongly and consistently correlated with performance on the medial temporal lobe task, but not the dorsolateral prefrontal task. The hypothesis that autism is related to dysfunction of the medial temporal lobe and related limbic structures, such as the orbital prefrontal cortex, is discussed.     

The effects of limbic lesions on locomotion and stereotypy elicited by dopamine agonists in the rat

The purpose of this experiment was to investigate the functional contributions of various limbic structures to locomotion and stereotypy induced by dopaminergic drugs. Female rats were randomly assigned to one of 5 groups (n = 10-14 rats/group) that received either a lesion of the hippocampus (colchicine + kainic acid), basolateral amygdala (quinolinic acid), frontal cortex (aspiration), nucleus accumbens (ibotenic acid), or served as unoperated controls. Beginning at least 2 weeks following surgery locomotion (measured as photocell beam breaks) elicited by D-amphetamine (0.0, 0.32, 1.0 and 3.2 mg/kg), SKF 82958 (0.0, 0.04, 0.08 and 0.16 mg/kg) or quinpirole (0.0, 0.25, 0.1 and 0.5 mg/kg) was determined. In agreement with previous results rats with hippocampal lesions were hyperactive in response to amphetamine. In comparison to these changes in drug-induced locomotion, lesions of the basolateral amygdala, and frontal cortex had only minor effects on drug-induced locomotion. Lesions of the nucleus accumbens produced consistent hyperactivity that was suppressed by doses of amphetamine or quinpirole that elicited behavioral stereotypy. These results provide evidence suggesting that, in comparison to other limbic structures that have substantial inputs to the nucleus accumbens, the hippocampus play a relatively prominent role in the modulation of drug-induced locomotion.     

Phencyclidine (PCP) acts at sigma sites to induce c-fos gene expression

Phencyclidine (PCP) is a compound that results in abnormal human behavior and has been proposed as a chemical model for schizophrenia. It was hypothesized that PCP induction of the immediate-early gene, c-fos, should be seen in areas associated with emotional behavior, such as the cortex and limbic system. It was also proposed that PCP may induce c-fos via the sigma receptor. PCP and two sigma ligands, 1,3-di(2-tolyl)guanidine (DTG) and pentazocine, were shown to induce c-fos in similar patterns. The three compounds abundantly induced c-fos in the cingulate, parietal, and piriform cortices and the midline structures of the thalamus and hypothalamus. Neither PCP nor the sigma ligands induced c-fos in the hippocampus. This suggests that PCP binding at NMDA receptors does not result in significant c-fos induction. Rimcazole, a putative sigma2 receptor antagonist, and other sigma ligands have been shown to ameliorate PCP stereotypic behavior. Rimcazole inhibited PCP c-fos induction in the cingulate and parietal cortices and DTG c-fos induction in the cingulate cortex. DTG shows both sigma1 and sigma2 binding affinity. Rimcazole failed to inhibit pentazocine c-fos induction. Pentazocine binds only to sigma1 receptors. This suggests that PCP may produce a significant fraction of its c-fos induction via sigma2 receptors.     

Early specification and autonomous development of cortical fields in the mouse hippocampus

Studies of the specification of distinct areas in the developing cerebral cortex have until now focused mainly on neocortex. We demonstrate that the hippocampus, an archicortical structure, offers an elegant, alternative system in which to explore cortical area specification. Individual hippocampal areas, called CA fields, display striking molecular differences in maturity. We use these distinct patterns of gene expression as markers of CA field identity, and show that the two major hippocampal fields, CA1 and CA3, are specified early in hippocampal development, during the period of neurogenesis. Two field-specific markers display consistent patterns of expression from the embryo to the adult. Presumptive CA1 and CA3 fields (Pca1, Pca3) can therefore be identified between embryonic days 14.5 and 15.5 in the mouse, a week before the fields are morphologically distinct. No other individual cortical areas have been detected by gene expression as early in development. Indeed, other features that distinguish between the CA fields appear after birth, indicating that mature CA field identity is acquired over at least 3 weeks. To determine if Pca1 and Pca3 are already specified to acquire mature CA field identities, the embryonic fields were isolated from further potential specification cues by maintaining them in slice culture. CA field development proceeds in slices of the entire embryonic hippocampus. More strikingly, slices restricted to Pca1 or Pca3 alone also develop appropriate mature features of CA1 or CA3. Pca1 and Pca3 are therefore able to develop complex characteristics of mature CA field identity autonomously, that is, without contact or innervation from other fields or other parts of the brain. Because Pca1 and Pca3 can be identified before major afferents grow into the hippocampus, innervation may also be unnecessary for the initial division of the hippocampus into separate fields. Providing a clue to the source of the true specifying signals, the earliest field markers appear first at the poles of the hippocampus, then progress inwards. General hippocampal development does not follow this pronounced pattern. We suggest that the sources of signals that specify hippocampal field identity lie close to the hippocampal poles, and that the signals operate first on cells at the poles, then move inwards.     

Central neural correlates of learned heart rate control during exercise: central command demystified

To identify the brain areas involved in central command, four monkeys were trained to attenuate the tachycardia of exercise while different brain sites affecting heart rate (HR) were simultaneously stimulated electrically. Among 24 brain sites located mostly in the limbic structures, we have identified four types of control systems that mediate cardiovascular and motor behavior during exercise. One system increases HR equivalently during both exercise and operantly controlled HR, whereas another increases HR during both tasks and abolishes operant HR control. In the third system, the effect of brain stimulation on HR is attenuated during exercise and during exercise with operantly controlled HR. The fourth system increases HR in both tasks, but its effect is significantly attenuated during operant HR control. We believe that this last system, which includes the mediodorsal nucleus, nucleus ventralis anterior, and cingulate cortex, plays a significant role in central command.     

Abortion--a subject kept in the dark

Acute experiment on rabbits (extracellular registration) studied influence of limbic cortex on neuron activity of Deuters nucleus before and after exposure to low-frequency vibration (5 Hz, 30 minutes). The authors discuss mechanisms underlying changes in activity and response of vestibular neutrons to electric simulation (5 and 60 Hz) of limbic cortex before and after vibration.