Electroencephalogram and event-related potentials in the selective attention paradigm as related to the levels of some metabolites in the prefrontal cortex

The results of preliminary analysis at the first stage of the study have demonstrated significant relationships between electrophysiological parameters and the levels of a number of metabolites (measured by proton magnetic resonance spectroscopy) in the dorsolateral prefrontal cortex of the left cerebral hemisphere. The observed relationships are assumed to be mediated by individual-specific characteristics of activation of this cerebral region and its contribution to information processing. The neurophysiological markers of the weakened functional state of the brain are associated with decreased levels of N-acetyl aspartate and choline-containing compounds and an increased level of creatin/phosphocreatin in the tested area of the left prefrontal cortex.     

Oxidative damage increases with age in a canine model of human brain aging

We assayed levels of lipid peroxidation, protein carbonyl formation, glutamine synthetase (GS) activity and both oxidized and reduced glutathione to study the link between oxidative damage, aging and beta-amyloid (Abeta) in the canine brain. The aged canine brain, a model of human brain aging, naturally develops extensive diffuse deposits of human-type Abeta. Abeta was measured in immunostained prefrontal cortex from 19 beagle dogs (4-15 years). Increased malondialdehyde (MDA), which indicates increased lipid peroxidation, was observed in the prefrontal cortex and serum but not in cerebrospinal fluid (CSF). Oxidative damage to proteins (carbonyl formation) also increased in brain. An age-dependent decline in GS activity, an enzyme vulnerable to oxidative damage, and in the level of glutathione (GSH) was observed in the prefrontal cortex. MDA level in serum correlated with MDA accumulation in the prefrontal cortex. Although 11/19 animals exhibited Abeta, the extent of deposition did not correlate with any of the oxidative damage measures, suggesting that each form of neuropathology accumulates in parallel with age. This evidence of widespread oxidative damage and Abeta deposition is further justification for using the canine model for studying human brain aging and neurodegenerative diseases.     

Dysfunction in a prefrontal substrate of sustained attention in schizophrenia

Regional brain metabolism was measured in normal subjects and patients with schizophrenia while they performed an auditory discrimination task designed to emphasize sustained attention. A direct relationship was found in the normal subjects between metabolic rate in the middle prefrontal cortex and accuracy of performance. The metabolic rate in the middle prefrontal cortex of patients with schizophrenia, even those who performed as well as normals, was found to be significantly lower than normal and unrelated to performance. The findings point to a role of the mid-prefrontal region in sustained attention and to dysfunction of this region in schizophrenia.     

Acute stress responsive RGS proteins in the mouse brain

Regulator of G-protein signaling (RGS) proteins play an important role in G-protein coupled receptor (GPCR) signaling and the activity of some GPCRs is modulated via RGS protein levels during stress response. The aim of this study was to investigate changes in RGS protein mRNA expressions in the mouse brain after 2h restraint stress. The mRNA level of 19 RGS proteins was analyzed using real-time PCR in six brain regions, which included the prefrontal cortex, amygdala, hippocampus, hypothalamus, striatum, and pituitary gland, from control and stressed mouse. We found that the level of mRNA of each RGS varied according to brain region and that two to eight RGS proteins exhibited changes in mRNA levels in each brain region by restraint stress. It was also revealed that RGS4 protein amount was consistent with mRNA level, indicating RGS4 protein may have regulatory roles in the acute stress response.     

Lateral prefrontal cortex: architectonic and functional organization

A comparison of the architecture of the human prefrontal cortex with that of the macaque monkey showed a very similar architectonic organization in these two primate species. There is no doubt that the prefrontal cortical areas of the human brain have undergone considerable development, but it is equally clear that the basic architectonic organization is the same in the two species. Thus, a comparative approach to the study of the functional organization of the primate prefrontal cortex is more likely to reveal the essential aspects of the various complex control processes that are the domain of frontal function. The lateral frontal cortex appears to be functionally organized along both a rostral-caudal axis and a dorsal-ventral axis. The most caudal frontal region, the motor region on the precentral gyrus, is involved in fine motor control and direct sensorimotor mappings, whereas the caudal lateral prefrontal region is involved in higher order control processes that regulate the selection among multiple competing responses and stimuli based on conditional operations. Further rostrally, the mid-lateral prefrontal region plays an even more abstract role in cognitive control. The mid-lateral prefrontal region is itself organized along a dorsal-ventral axis of organization, with the mid-dorsolateral prefrontal cortex being involved in the monitoring of information in working memory and the mid-ventrolateral prefrontal region being involved in active judgments on information held in posterior cortical association regions that are necessary for active retrieval and encoding of information.     

Uniquely human social cognition

Recent data identify distinct components of social cognition associated with five brain regions. In posterior temporal cortex, the extrastriate body area is associated with perceiving the form of other human bodies. A nearby region in the posterior superior temporal sulcus is involved in interpreting the motions of a human body in terms of goals. A distinct region at the temporo-parietal junction supports the uniquely human ability to reason about the contents of mental states. Medial prefrontal cortex is divided into at least two subregions. Ventral medial prefrontal cortex is implicated in emotional empathy, whereas dorsal medial prefrontal cortex is implicated in the uniquely human representation of triadic relations between two minds and an object, supporting shared attention and collaborative goals.     

Reading hidden intentions in the human brain

When humans are engaged in goal-related processing, activity in prefrontal cortex is increased. However, it has remained unclear whether this prefrontal activity encodes a subject's current intention. Instead, increased levels of activity could reflect preparation of motor responses, holding in mind a set of potential choices, tracking the memory of previous responses, or general processes related to establishing a new task set. Here we study subjects who freely decided which of two tasks to perform and covertly held onto an intention during a variable delay. Only after this delay did they perform the chosen task and indicate which task they had prepared. We demonstrate that during the delay, it is possible to decode from activity in medial and lateral regions of prefrontal cortex which of two tasks the subjects were covertly intending to perform. This suggests that covert goals can be represented by distributed patterns of activity in the prefrontal cortex, thereby providing a potential neural substrate for prospective memory. During task execution, most information could be decoded from a more posterior region of prefrontal cortex, suggesting that different brain regions encode goals during task preparation and task execution. Decoding of intentions was most robust from the medial prefrontal cortex, which is consistent with a specific role of this region when subjects reflect on their own mental states.     

Tyrosine Hydroxylase Activation in Mesocortical 3,4-Dihydroxyphenylethylamine Neurons Following Footshock

Mild electric footshock resulted in activation of tyrosine hydroxylase (TH) in prefrontal cortex of mice and rats. In mice, the activation was also observed following restraint. Shock-evoked activation of prefrontal cortex TH was characterized by a decrease of apparent Km for the pterin cofactor 6-methyl-5,6,7,8-tetrahydropterin and an increase of Vmax. Activation of prefrontal cortical TH was also demonstrated in vitro following preincubation under conditions that activate cyclic AMP-dependent protein kinase. Treatment of mice with the noradrenergic neurotoxin N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP-4) caused a 70% decrease in prefrontal cortex norepinephrine levels but had no significant effect on the activity of TH in that brain region. Footshock resulted in the activation of prefrontal cortex TH of DSP-4-treated mice, suggesting that shock-evoked activation of the enzyme occurs in terminals of mesocortical 3,4-dihydroxyphenylethylamine neurons.     

Structural rearrangements of the cerebral cortex in children and adolescents

The cortical formations of the brain involved in visual functions (the occipital and temporo-parieto- occipital areas, the oculomotor area of the prefrontal cortex), as well as the motor cortex in the representation zone of the arm and the medial region of the frontal cortex adjacent to the limbic lobe, were studied in post-mortem material. The thickness of the cortex and cortical layer III, the sizes of pyramidal neurons, the specific volumes of neurons and intracortical vessels were studied in subjects of both sexes, from birth to the age of 20 years, at yearly intervals (103 observations) using histological techniques, computer morphometric and stereological analysis. The thickness of the cortex of the cerebral hemispheres was observed to intensively increase from birth to the age of 3 years in the occipital, temporo-parieto-occipital and prefrontal cortical areas involved in visual recognition processes. The increase in thickness of the cerebral cortex continues until the age of 6 in the occipital cortex and in the oculomotor area, until the age of 7 years in the temporo-parietooccipital area and the medial prefrontal area, and until the age of 8–9 years in the motor cortex. The sizes of pyramidal neurons increase until the age of 6 years in the motor cortex, until the age of 8 years on the medial surface of the frontal lobe, and until the age of 9–10 years in the temporo-parieto-occipital area and in the dorsolateral area of the prefrontal cortex. The specific volume of neurons and blood vessels in the cortex of the cerebral hemispheres decreases and the volume of intracortical fibers increases throughout the ascending ontogeny, which is manifested most intensively in the prefrontal cortex.     

Cerebral Inefficient Activation in Schizophrenia Patients and Their Unaffected Parents during the N-Back Working Memory Task: A Family fMRI Study

Background

It has been suggested that working memory deficits is a core feature of symptomatology of schizophrenia, which can be detected in patients and their unaffected relatives. The impairment of working memory has been found related to the abnormal activity of human brain regions in many functional magnetic resonance imaging (fMRI) studies. This study investigated how brain region activation was altered in schizophrenia and how it was inherited independently from performance deficits.

Method

The authors used fMRI method during N-back task to assess working memory related cortical activation in four groups (N = 20 in each group, matching task performance, age, gender and education): schizophrenic patients, their unaffected biological parents, young healthy controls for the patients and older healthy controls for their parents.

Results

Compared to healthy controls, patients showed an exaggerated response in the right dorsolateral prefrontal cortex (brodmann area [BA] 46) and bilateral ventrolateral prefrontal cortex, and had reduced activation in bilateral dorsolateral prefrontal cortex (BA 9). In the conjunction analysis, the effect of genetic risk (parents versus older control) shared significantly overlapped activation with effect of disease (patients versus young control) in the right middle frontal gyrus (BA 46) and left inferior parietal gyrus (BA 40).

Conclusions

Physiological inefficiency of dorsal prefrontal cortex and compensation involvement of ventral prefrontal cortex in working memory function may one physiological characteristics of schizophrenia. And relatively inefficient activation in dorsolateral prefrontal cortex probably can be a promising intermediate phenotype for schizophrenia.     

内侧前额叶与社会认知

早期的研究表明杏仁核、前额叶、颞上沟、前扣带回等与人类的社会认知活动有关;随着多种新技术的应用。越来越多的研究发现其它一些脑区结构(如岛叶、基底节、白质等)也与社会认知和行为有关。本文综述了内侧前额叶在社会认知中的作用,重点介绍了内侧前额叶在心灵理论、情绪认知、社会推理与决策、道德判断、自我认知等社会认知活动中的作用。未来研究希望能从整体和动态上认识内侧前额叶在社会认知活动中的作用。     

Altered Resting-State Functional Connectivity of the Frontal-Striatal Reward System in Social Anxiety Disorder

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.     

Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with L-[beta-11C]DOPA

Loss of dopamine synthesis in the striatum with normal human aging has been observed in the postmortem brain. To investigate whether there is age-associated change in dopamine synthesis in the extrastriatal brain regions similar to that in the striatum, positron emission tomography studies with (11)C-labelled l-DOPA were performed on 21 normal healthy male subjects (age range 20-67 years). Decline in the tissue fraction of gray matter per region of interest was also investigated. The overall uptake rate constant for each region of interest was quantified by the Patlak plot method using the occipital cortex as reference region. Regions of interest were set on the dorsolateral prefrontal cortex, lateral temporal cortex, medial temporal cortex, occipital cortex, parietal cortex, anterior cingulate, thalamus, midbrain, caudate nucleus, and putamen. Test-retest analysis indicated good reproducibility of the overall uptake rate constant. Significant age-related declines of dopamine synthesis were observed in the striatum and extrastriatal regions except midbrain. The decline in the overall uptake rate constant was more prominent than in the tissue fraction of gray matter. These results indicate that the previously demonstrated age-related decline in striatal dopamine synthesis extends to several extrastriatal regions in normal human brain.     

Different roles of dopamine and serotonin in conditioned passive avoidance response of rats

Deamination of dopamine and serotonin by monoamine oxidase was studied in the prefrontal cortex, striatum, hippocampus and amygdaloid complex of the brain of rats during retrieval of conditioned passive avoidance response. Changes in the dopamine and serotonin metabolism were observed in different brain structures. A decrease in dopamine-deaminating activity of monoamine oxidase was found in the hippocampus, striatum and prefrontal cortex. At the same time, serotonin-deaminating activity of the enzyme was decreased in the striatum and increased in the amygdaloid complex, whereas it did not change in the prefrontal cortex and hippocampus. The observed changes in dopamine metabolism in the prefrontal cortex and hippocampus and serotonin metabolism in the amygdaloid complex indicate that dopamine and serotonin are involved in the regulation of two different processes mediating the memory trace retrieval. Dopamine is involved in neuronal mechanisms of information processes providing the strategy of behavior, whereas serotonin is related to emotional mechanisms of memory.     

DARPP-32 and NCS-1 Expression is not Altered in Brains of Rats Treated with Typical or Atypical Antipsychotics

Dopamine-mediated neurotransmission imbalances are associated with several psychiatry illnesses, such as schizophrenia. Recently it was demonstrated that two proteins involved in dopamine signaling are altered in prefrontal cortex (PFC) of schizophrenic patients. DARPP-32 is a key downstream effector of intracellular signaling pathway and is downregulated in PFC of schizophrenic subjects. NCS-1 is a neuronal calcium sensor that can inhibit dopamine receptor D₂ internalization and is upregulated in PFC of schizophrenic subjects. It is well known that dopamine D₂ receptor is the main target of antipsychotic. Therefore, our purpose was to study if chronic treatment with typical or atypical antipsychotics induced alterations in DARPP-32 and NCS-1 expression in five brain regions: prefrontal cortex, hippocampus, striatum, cortex and cerebellum. We did not find any changes in DARPP-32 and NCS-1 protein expression in any brain region investigated.     

Broca's area and the hierarchical organization of human behavior

The prefrontal cortex subserves executive control, i.e., the organization of action or thought in relation to internal goals. This brain region hosts a system of executive processes extending from premotor to the most anterior prefrontal regions that governs the temporal organization of behavior. Little is known, however, about the prefrontal executive system involved in the hierarchical organization of behavior. Here, we show using magnetic resonance imaging in humans that the posterior portion of the prefrontal cortex, including Broca's area and its homolog in the right hemisphere, contains a system of executive processes that control start and end states and the nesting of functional segments that combine in hierarchically organized action plans. Our results indicate that Broca's area and its right homolog process hierarchically structured behaviors regardless of their temporal organization, suggesting a fundamental segregation between prefrontal executive systems involved in the hierarchical and temporal organization of goal-directed behaviors.     

Memory trace in prefrontal cortex: theory for the cognitive switch

The dorsolateral prefrontal cortex in human and non-human primates functions as the highest-order executor for the perception-action cycle. According to this view, when perceptual stimuli from the environment are novel or complex, the dorsolateral prefrontal cortex serves to set consciously a goal-directed scheme which broadly determines an action repertory to meet the particular demand from the environment. In this respect, the dorsolateral prefrontal cortex is a short-term activation device with the properties of a cognitive switch', because it couples a particular set of perceptual stimuli to a particular set of actions. Here, I suggest that, in order for the organism to react systematically to the environment, neural traces for the switch function must be stored in the brain. Thus, the highest-order, perception-action interface function of the dorsolateral prefrontal cortex per se depends on permanently stored neural traces in the dorsolateral prefrontal cortex and related structures. Such a memory system may be located functionally between two of the well-documented memory systems in the brain: the declarative memory system and the procedural memory system. Finally, based on available neurophysiological data, the possible mechanisms underlying the formation of cognitive switch traces are proposed.     

BDNF Level in the Rat Prefrontal Cortex Increases Following Chronic but Not Acute Treatment with Duloxetine, a Dual Acting Inhibitor of Noradrenaline and Serotonin Re-uptake

Aims Brain-Derived Neurotrophic Factor (BDNF) has a central role in neuronal survival, differentiation, and plasticity. The brain level of BDNF is changed by several mood stabilizers and antidepressant drugs acting on neurotransmitters such as noradrenaline and serotonin. We investigated the effects of acute and chronic treatment with Duloxetine, a new drug blocking the re-uptake of serotonin and noradrenaline (SNRI), on BDNF level in the prefrontal cortex, cerebrospinal fluid, plasma, and serum. Methods Wistar male rats were treated with acute (single treatment) and chronic oral administration (14 days) of different concentrations of Duloxetine (10, 30, and 100 mg/kg/day). At the end of the treatment periods, samples of blood, CSF and the prefrontal cortex were collected. BDNF levels were measured by ELISA. Levels of mature and precursor form of BDNF were measured by Western blot analysis. Results Animals treated with the Duloxetine at all concentrations and examined after 1 and 24 h (single treatment) did not reveal a significant change in the total BDNF level. In animals treated for 14 days with Duloxetine at 30 and 100 mg/kg, the total BDNF level increased significantly in the prefrontal cortex and CSF, but not in the plasma and serum. Using a specific antibody and Western blot we showed that the mature, but not the precursor, form of BDNF was significantly increased in the prefrontal cortex of rats treated for 14 days with Duloxetine at 30 mg/kg/day. Conclusions Our results show a major finding that repeated, but not single, Duloxetine treatment increases the level of BDNF in the prefrontal cortex. Claudio Mannari and Nicola Origlia are contributed equally to this work.