In pneumococcal meningitis a novel water-soluble inhibitor of matrix metalloproteinases and TNF-alpha converting enzyme attenuates seizures and injury of the cerebral cortex

Matrix metalloproteinases (MMPs) and TNF-alpha converting enzyme (TACE) contribute to the pathophysiology of bacterial meningitis. To date, MMP-inhibitors studied in models of meningitis were compromised by their hydrophobic nature. We investigated the pharmacokinetics and the effect of TNF484, a water-soluble hydroxamate-based inhibitor of MMP and TACE, on disease parameters and brain damage in a neonatal rat model of pneumococcal meningitis. At 1 mg/kg q6h TNF484 reduced soluble TNF-alpha and the collagen degradation product hydroxyproline in the cerebrospinal fluid. Clinically, TNF484 attenuated the incidence of seizures and was neuroprotective in the cortex. Water-soluble MMP-inhibitors may hold promise in the therapy of bacterial meningitis.

Grey matter volumetric changes related to recovery from hand paresis after cortical sensorimotor stroke

Preclinical studies using animal models have shown that grey matter plasticity in both perilesional and distant neural networks contributes to behavioural recovery of sensorimotor functions after ischaemic cortical stroke. Whether such morphological changes can be detected after human cortical stroke is not yet known, but this would be essential to better understand post-stroke brain architecture and its impact on recovery. Using serial behavioural and high-resolution magnetic resonance imaging (MRI) measurements, we tracked recovery of dexterous hand function in 28 patients with ischaemic stroke involving the primary sensorimotor cortices. We were able to classify three recovery subgroups (fast, slow, and poor) using response feature analysis of individual recovery curves. To detect areas with significant longitudinal grey matter volume (GMV) change, we performed tensor-based morphometry of MRI data acquired in the subacute phase, i.e. after the stage compromised by acute oedema and inflammation. We found significant GMV expansion in the perilesional premotor cortex, ipsilesional mediodorsal thalamus, and caudate nucleus, and GMV contraction in the contralesional cerebellum. According to an interaction model, patients with fast recovery had more perilesional than subcortical expansion, whereas the contrary was true for patients with impaired recovery. Also, there were significant voxel-wise correlations between motor performance and ipsilesional GMV contraction in the posterior parietal lobes and expansion in dorsolateral prefrontal cortex. In sum, perilesional GMV expansion is associated with successful recovery after cortical stroke, possibly reflecting the restructuring of local cortical networks. Distant changes within the prefrontal-striato-thalamic network are related to impaired recovery, probably indicating higher demands on cognitive control of motor behaviour.

Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors

Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

From episodic to habitual prospective memory: ERP-evidence for a linear transition

Performing a prospective memory task repeatedly changes the nature of the task from episodic to habitual. The goal of the present study was to investigate the neural basis of this transition. In two experiments, we contrasted event-related potentials (ERPs) evoked by correct responses to prospective memory targets in the first, more episodic part of the experiment with those of the second, more habitual part of the experiment. Specifically, we tested whether the early, middle, or late ERP-components, which are thought to reflect cue detection, retrieval of the intention, and post-retrieval processes, respectively, would be changed by routinely performing the prospective memory task. The results showed a differential ERP effect in the middle time window (450 - 650 ms post-stimulus). Source localization using low resolution brain electromagnetic tomography analysis (LORETA) suggests that the transition was accompanied by an increase of activation in the posterior parietal and occipital cortex. These findings indicate that habitual prospective memory involves retrieval processes guided more strongly by parietal brain structures. In brief, the study demonstrates that episodic and habitual prospective memory tasks recruit different brain areas.

Delay of cortical thinning in very preterm born children

BACKGROUND: Cortical gray matter thinning occurs during childhood due to pruning of inefficient synaptic connections and an increase in myelination. Preterms show alterations in brain structure, with prolonged maturation of the frontal lobes, smaller cortical volumes and reduced white matter volume. These findings give rise to the question if there is a differential influence of age on cortical thinning in preterms compared to controls. AIMS: To investigate the relationship between age and cortical thinning in school-aged preterms compared to controls. STUDY DESIGN AND OUTCOME MEASURES: The automated surface reconstruction software FreeSurfer was applied to obtain measurements of cortical thickness based on T1-weighted MRI images. SUBJECTS: Forty-one preterms (<32weeks gestational age and/or <1500g birth weight) and 30 controls were included in the study (7-12years). RESULTS: In preterms, age correlated negatively with cortical thickness in right frontal, parietal and inferior temporal regions. Furthermore, young preterms showed a thicker cortex compared to old preterms in bilateral frontal, parietal and temporal regions. In controls, age was not associated with cortical thickness. CONCLUSION: In preterms, cortical thinning still seems to occur between the age of 7 and 12years, mainly in frontal and parietal areas whereas in controls, a substantial part of cortical thinning appears to be completed before they reach the age of 7years. These data indicate slower cortical thinning in preterms than in controls.

Diminishing parochialism in intergroup conflict by disrupting the right temporo-parietal junction.

Individuals react to violation of social norms by outgroup members differently than to transgressions of those same norms by ingroup members: namely outgroup perpetrators are punished much more harshly than ingroup perpetrators. This parochial punishment pattern has been observed and extensively studied in social psychology and behavioral economics. Despite progress in recent years, however, little is known about the neural underpinnings of this intergroup bias. Here, we demonstrate by means of transcranial magnetic stimulation (TMS) that the transient disruption of the right, but not the left temporo-parietal junction (TPJ), reduces parochial punishment in a third-party punishment paradigm with real social groups. Moreover, we show that this observed TMS effect on parochial punishment is mediated by a classical punishment motive, i.e. retaliation. Finally, our data suggests that a change in perspective-taking might be the underlying mechanism that explains the impact of right TPJ disruption on retaliation motivation and parochial punishment. These findings provide the first causal evidence that the right TPJ plays a pivotal role in the implementation of parochial behaviors.

Impartiality in humans is predicted by brain structure of dorsomedial prefrontal cortex.

The moral force of impartiality (i.e. the equal treatment of all human beings) is imperative for providing justice and fairness. Yet, in reality many people become partial during intergroup interactions; they demonstrate a preferential treatment of ingroup members and a discriminatory treatment of outgroup members. Some people, however, do not show this intergroup bias. The underlying sources of these inter-individual differences are poorly understood. Here we demonstrate that the larger the gray matter volume and thickness of the dorsomedial prefrontal cortex (DMPFC), the more individuals in the role of an uninvolved third-party impartially punish outgroup and ingroup perpetrators. Moreover, we show evidence for a possible mechanism that explains the impact of DMPFC's gray matter volume on impartiality, namely perspective-taking. Large gray matter volume of DMPFC seems to facilitate equal perspective-taking of all sides, which in turn leads to impartial behavior. This is the first evidence demonstrating that brain structure of the DMPFC constitutes an important source underlying an individual's propensity for impartiality.

Dorsolateral and ventromedial prefrontal cortex orchestrate normative choice.

Humans are noted for their capacity to over-ride self-interest in favor of normatively valued goals. We examined the neural circuitry that is causally involved in normative, fairness-related decisions by generating a temporarily diminished capacity for costly normative behavior, a 'deviant' case, through non-invasive brain stimulation (repetitive transcranial magnetic stimulation) and compared normal subjects' functional magnetic resonance imaging signals with those of the deviant subjects. When fairness and economic self-interest were in conflict, normal subjects (who make costly normative decisions at a much higher frequency) displayed significantly higher activity in, and connectivity between, the right dorsolateral prefrontal cortex (DLPFC) and the posterior ventromedial prefrontal cortex (pVMPFC). In contrast, when there was no conflict between fairness and economic self-interest, both types of subjects displayed identical neural patterns and behaved identically. These findings suggest that a parsimonious prefrontal network, the activation of right DLPFC and pVMPFC, and the connectivity between them, facilitates subjects' willingness to incur the cost of normative decisions.

The mentalizing network orchestrates the impact of parochial altruism on social norm enforcement.

Parochial altruism - a preference for altruistic behavior towards ingroup members and mistrust or hostility towards outgroup members--is a pervasive feature in human society and strongly shapes the enforcement of social norms. Since the uniqueness of human society critically depends on the enforcement of norms, the understanding of the neural circuitry of the impact of parochial altruism on social norm enforcement is key, but unexplored. To fill this gap, we measured brain activity with functional magnetic resonance imaging (fMRI) while subjects had the opportunity to punish ingroup members and outgroup members for violating social norms. Findings revealed that subjects' strong punishment of defecting outgroup members is associated with increased activity in a functionally connected network involved in sanction-related decisions (right orbitofrontal gyrus, right lateral prefrontal cortex, right dorsal caudatus). Moreover, the stronger the connectivity in this network, the more outgroup members are punished. In contrast, the much weaker punishment of ingroup members who committed the very same norm violation is associated with increased activity and connectivity in the mentalizing-network (dorsomedial prefrontal cortex, bilateral temporo-parietal junction), as if subjects tried to understand or justify ingroup members' behavior. Finally, connectivity analyses between the two networks suggest that the mentalizing-network modulates punishment by affecting the activity in the right orbitofrontal gyrus and right lateral prefrontal cortex, notably in the same areas showing enhanced activity and connectivity whenever third-parties strongly punished defecting outgroup members.

Chronometric features of processing unpleasant stimuli: a functional MRI-based transcranial magnetic stimulation study.

The quick identification of potentially threatening events is a crucial cognitive capacity to survive in a changing environment. Previous functional MRI data revealed the right dorsolateral prefrontal cortex and the region of the left intraparietal sulcus (IPS) to be involved in the perception of emotionally negative stimuli. For assessing chronometric aspects of emotion processing, we applied transcranial magnetic stimulation above these areas at different times after negative and neutral picture presentation. An interference with emotion processing was found with transcranial magnetic stimulation above the dorsolateral prefrontal cortex 200-300 ms and above the left intraparietal sulcus 240/260 ms after negative stimuli. The data suggest a parallel and conjoint involvement of prefrontal and parietal areas for the identification of emotionally negative stimuli.

Neural correlate of spatial presence in an arousing and noninteractive virtual reality: an EEG and psychophysiology study

Using electroencephalography (EEG), psychophysiology, and psychometric measures, this is the first study which investigated the neurophysiological underpinnings of spatial presence. Spatial presence is considered a sense of being physically situated within a spatial environment portrayed by a medium (e.g., television, virtual reality). Twelve healthy children and 11 healthy adolescents were watching different virtual roller coaster scenarios. During a control session, the roller coaster cab drove through a horizontal roundabout track. The following realistic roller coaster rides consisted of spectacular ups, downs, and loops. Low-resolution brain electromagnetic tomography (LORETA) and event-related desynchronization (ERD) were used to analyze the EEG data. As expected, we found that, compared to the control condition, experiencing a virtual roller coaster ride evoked in both groups strong SP experiences, increased electrodermal reactions, and activations in parietal brain areas known to be involved in spatial navigation. In addition, brain areas that receive homeostatic afferents from somatic and visceral sensations of the body were strongly activated. Most interesting, children (as compared to adolescents) reported higher spatial presence experiences and demonstrated a different frontal activation pattern. While adolescents showed increased activation in prefrontal areas known to be involved in the control of executive functions, children demonstrated a decreased activity in these brain regions. Interestingly, recent neuroanatomical and neurophysiological studies have shown that the frontal brain continues to develop to adult status well into adolescence. Thus, the result of our study implies that the increased spatial presence experience in children may result from the not fully developed control functions of the frontal cortex.

Tonic activity level in the right prefrontal cortex predicts individuals' risk taking

Human risk taking is characterized by a large amount of individual heterogeneity. In this study, we applied resting-state electroencephalography, which captures stable individual differences in neural activity, before subjects performed a risk-taking task. Using a source-localization technique, we found that the baseline cortical activity in the right prefrontal cortex predicts individual risk-taking behavior. Individuals with higher baseline cortical activity in this brain area display more risk aversion than do other individuals. This finding demonstrates that neural characteristics that are stable over time can predict a highly complex behavior such as risk-taking behavior and furthermore suggests that hypoactivity in the right prefrontal cortex might serve as a dispositional indicator of lower regulatory abilities, which is expressed in greater risk-taking behavior.

Rivastigmine effects on EEG spectra and three-dimensional LORETA functional imaging in Alzheimer's disease

OBJECTIVE The objective of the study is to investigate the electrocortical and the global cognitive effects of 3 months rivastigmine medication in a group of mild to moderate Alzheimer's disease patients. MATERIALS AND METHODS Multichannel EEG and cognitive performances measured with the Mini Mental State Examination in a group of 16 patients with mild to moderate Alzheimer's Disease were collected before and 3 months after the onset of rivastigmine medication. RESULTS Spectral analysis of the EEG data showed a significant power decrease in the delta and theta frequency bands during rivastigmine medication, i.e., a shift of the power spectrum towards 'normalization'. Three-dimensional low resolution electromagnetic tomography (LORETA) functional imaging localized rivastigmine effects in a network that includes left fronto-parietal regions, posterior cingulate cortex, bilateral parahippocampal regions, and the hippocampus. Moreover, a correlation analysis between differences in the cognitive performances during the two recordings and LORETA-computed intracortical activity showed, in the alpha1 frequency band, better cognitive performance with increased cortical activity in the left insula. CONCLUSION The results point to a 'normalization' of the EEG power spectrum due to medication, and the intracortical localization of these effects showed an increase of cortical activity in frontal, parietal, and temporal regions that are well-known to be affected in Alzheimer's disease. The topographic convergence of the present results with the memory network proposed by Vincent et al. (J. Neurophysiol. 96:3517-3531, 2006) leads to the speculation that in our group of patients, rivastigmine specifically activates brain regions that are involved in memory functions, notably a key symptom in this degenerative disease.

Disruption of right prefrontal cortex by low-frequency repetitive transcranial magnetic stimulation induces risk-taking behavior

Decisions require careful weighing of the risks and benefits associated with a choice. Some people need to be offered large rewards to balance even minimal risks, whereas others take great risks in the hope for an only minimal benefit. We show here that risk-taking is a modifiable behavior that depends on right hemisphere prefrontal activity. We used low-frequency, repetitive transcranial magnetic stimulation to transiently disrupt left or right dorsolateral prefrontal cortex (DLPFC) function before applying a well known gambling paradigm that provides a measure of decision-making under risk. Individuals displayed significantly riskier decision-making after disruption of the right, but not the left, DLPFC. Our findings suggest that the right DLPFC plays a crucial role in the suppression of superficially seductive options. This confirms the asymmetric role of the prefrontal cortex in decision-making and reveals that this fundamental human capacity can be manipulated in normal subjects through cortical stimulation. The ability to modify risk-taking behavior may be translated into therapeutic interventions for disorders such as drug abuse or pathological gambling.

Lateral prefrontal cortex and self-control in intertemporal choice.

Disruption of function of left, but not right, lateral prefrontal cortex (LPFC) with low-frequency repetitive transcranial magnetic stimulation (rTMS) increased choices of immediate rewards over larger delayed rewards. rTMS did not change choices involving only delayed rewards or valuation judgments of immediate and delayed rewards, providing causal evidence for a neural lateral-prefrontal cortex-based self-control mechanism in intertemporal choice.