Current Topics in Medicinal Chemistry - Volume 12, Issue 21, 2012

Theory of Mind, the ability to understand the potential mental states and intentions of others, represents a relevant aspect of social cognition, with high impact on the capacity to interact within the social world. This very human ability has been one of the focuses of neuroscience research in the past decades and data from neuroimaging studies allowed to identify a Theory of Mind network and to formulate a neurobiological model. Concurrent neuropsychiatric studies showed that Theory of Mind is differently impaired in several conditions, among these, in schizophrenia, a disease characterized by functional and social disability. This paper addresses the issue of neurofunctional correlates of Theory of Mind deficits in schizophrenia, reviewing functional imaging studies of the past ten years comparing schizophrenia patients to healthy controls. Several differences in hemodynamic response between patients and controls were observed in the areas known to be critically involved in social cognition, such as the medial prefrontal cortex, temporal cortex surrounding superior temporal sulcus and temporo-parietal junction and cingulate cortex. Results are promising, however they are still heterogeneous. The reported variability could depend on factors related to the construct of Theory of Mind itself, technical aspects and psychopathological/physiopathological mechanisms and needs to be further addressed by future studies.

22q11.2 Deletion syndrome (22q11DS) is the most common known recurrent copy-number variant disorder. It is also the most common known genetic risk factor for schizophrenia. The greater homogeneity of subjects with schizophrenia in 22q11DS compared with schizophrenia in the wider non-deleted population may help to identify much needed information on neuroanatomical substrates, and neurochemical and neurofunctional mechanisms that may modulate the risk for schizophrenia. Identification of the underlying pathophysiology creates opportunities for developing genotype-specific, biology-based and targeted treatments to prevent, delay or minimize the severity of schizophrenia in both 22q11DS and the wider non-deleted population. This article reviews neuroimaging studies that focused on brain structure and function in this high-risk population, with particular attention to schizophrenia research. We also discuss the evidence on the role of candidate genes within the 22q11.2 region, with particular reference to catechol-O-methyl transferase (COMT) and proline dehydrogenase (PRODH).

Physiological enzymatic cleavage of membrane phospholipids by phospholipase A2 (PLA2) results in normal levels of phosphomonoester and phosphodiester, by which a normal dopamine neurotransmission is maintained. Data from postmortem tissue and in vivo imaging studies suggest that increased activity of intracellular calcium-independent PLA2 (iPLA2) in the brain of schizophrenic patients might accelerate the breakdown of membrane phospholipids and alter the properties of neuronal membranes, which in turn contributes to a hypodopaminergy. Alterations in PLA2 activity are probably genetically determined and represent a possible pharmacological target for Schizophrenia.

A large body of neuroimaging literature suggests that distributed regions in the brain form coordinated largescale networks that show reliable patterns of connectivity when observed using either functional or structural magnetic resonance imaging (MRI) methods. Functional activation within these networks provides a robust and reliable representation of dynamic brain states observed during information processing. One such network comprised of anterior frontoinsular cortex (aFI) and anterior cingulate cortex (ACC) is called the Salience Network (SN). SN has been identified as a system that enables the switch between various dynamic brain states. SN dysfunction has been proposed as a mechanistic model for several core symptoms of schizophrenia. In this review, we explore how various risk factors of schizophrenia could operate through the dysfunctional SN to generate symptoms of psychosis. We also consider the putative neurochemical basis for the SN dysfunction in schizophrenia, and suggest that the SN dysfunction is a viable therapeutic target for a combined pharmacological and cognitive training treatment approach. This combination approach, termed as Brain Network Modulation, could exploit neuronal plasticity to reverse a key pathophysiological deficit in schizophrenia.

Schizophrenia is a complex epigenetic puzzle, the antecedents of which are presumed to lie in neurodevelopmental dysmaturation. This dysmaturation has an impact on children and adolescents at genetic risk for schizophrenia. In this framework, normative mechanisms of brain development that are highly dynamic in adolescence are likely to be disrupted in the at-risk adolescent brain. It is likely that what is affected is the integrity of brain networks that sub-serve fundamental domains of function such as sustained attention. Notably, expansion in proficiency in sustained attention that is characteristic of typical development is likely to be compromised in adolescents at risk for schizophrenia. This confluence of at-risk adolescents and neuro-behavioral domains of inquiry is discussed. We outline the evidence for developmental antecedents of schizophrenia, and their bases in systems and molecular mechanisms in the brain. Then we juxtapose these results against neuro-behavioral evidence of attention deficits in high-risk populations, and fMRI evidence of dysfunctional responses in critical brain regions. We end by advocating the application of systems-based approaches toward understanding the progression of network dysfunction in the adolescent risk-state.

Aim: In this paper, we provide an update on the conceptual issues of psychiatric neuroimaging, especially in the light of the current reductive claims of the eliminative physicalism. Argument: our argument is developed on three stages. The first is to highlight the crucial importance of phenomenological psychopathology and person-centered approach, which remains underestimated; the second is to bring forward the view that functional neuroimaging is relevant to the area of ‘translation’ in the mind-brain debate. The third point is to present a critical analysis of the shortcomings in structural and functional neuroimaging from methodological and epistemological perspectives. Conclusion: a novel paradigm for translational cross-validation among neuroscience, psychopathology and clinical psychology is presented.

Schizophrenia has been historically characterized by the presence of positive symptomatology, however, decades of research highlight the importance of cognitive deficits in this disorder. At present, cognitive impairments remain one of the most important unmet therapeutic needs in schizophrenia. The prefrontal cortex (PFC) controls a large number of higher brain functions altered in a variety of psychiatric disorders, including schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of current atypical antipsychotics. Functional studies also show that these medications act at PFC level to increase dopamine neurotransmission in the mesocortical pathway. Here we focus on monoaminergic molecular targets that are actively being explored as potential therapeutic agents in the basic and clinical cognitive neuroscience research, to support the development of co-treatments used in conjunction with antipsychotic medications. These targets include dopamine and serotonin receptors in the prefrontal cortex, as well as elements of the noradrenergic system.

The advent of molecular neuroimaging has greatly impacted on understanding the neurochemical changes occurring in the CNS from subjects with psychiatric disorders, especially schizophrenia. This review focuses on the outcomes from studies using positron emission tomography and single photon emission computer tomography that have measure levels of neurotransmitter receptors and transporters in the CNS from subjects with schizophrenia. One outcome from such studies is the confirmation of a number of findings using postmortem tissue, but in the case of neuroimaging, using drug naïve and drug free subjects. These findings add weight to the argument that findings from postmortem studies are not an artifact of tissue processing or a simple drug effect. However, there are some important unique findings from studies using neuroimaging studies. These include evidence to suggest that in schizophrenia there are alterations in dopamine synthesis and release, which are not accompanied by an appropriate down-regulation of dopamine D2 receptors. There are also data that would support the notion that decreased levels of serotonin 2A receptors may be an early marker of the onset of schizophrenia. Whilst there is a clear need for on-going development of neuroimaging ligands to expand the number of targets that can be studied and to increase cohort sizes in neuroimaging studies to give power to the analyses of the resulting data, current studies show that existing neuroimaging studies have already extended our understanding of the underlying pathophysiology of psychiatric disorders such as schizophrenia.

The tremendous heterogeneity in the clinical symptoms and cognitive/emotional deficits seen in patients with schizophrenia has made it challenging to determine the underlying pathogenesis of the illness. One leading hypothesis that has come to the forefront over the past several decades is that schizophrenia is caused by aberrant connectivity between brain regions. In fact, a new field of connectomics has emerged to study the effects of brain connectivity in health and illness. It is known that schizophrenia is highly heritable, although in the search for the underlying genetic factors we have only scratched the tips of the omics icebergs. One technique to help identify underlying genetic factors is the use of heritable intermediate phenotypes, or endophenotypes. Endophenotypes provide mechanisms to study the genetic underpinnings of the disorder by focusing on measureable traits that are more proximal to gene regulation and expression than are symptoms. Thus, the goal of this paper is to conduct a critical review of the evidence linking both structural and functional connectivity as an endophenotype for schizophrenia.

Schizophrenia has been conceptualized as a disorder of altered brain connectivity (i.e. dysconnectivity). Until relatively recently, it was not feasible to test dysconnectivity hypotheses of schizophrenia in vivo. Resting-state functional magnetic resonance imaging (fMRI) is a powerful tool for mapping functional networks of the brain, such as the default mode network (DMN), and investigating the systems-level pathology of neurological and psychiatric disorders. In this article, we review the latest findings from resting-state fMRI studies on schizophrenia. Despite the wide array of methods used and heterogeneity of patient samples, several tentative conclusions may be drawn from the existing literature. 1) Connectivity of the DMN is altered in schizophrenia. Findings vary across studies; however, a majority of investigations reported hyper-connectivity of the DMN. 2) Resting-state connectivity of the prefrontal cortex (PFC) is reduced in schizophrenia, particularly intra-PFC connectivity. 3) Cortical-subcortical networks, including thalamocortical, frontolimbic, and cortico-cerebellar networks are altered in schizophrenia. 4) Preliminary findings indicate that functional connectivity within auditory/language networks and the basal ganglia is related to specific clinical symptoms, including auditory- verbal hallucinations and delusions. 5) Whole-brain network topology measures based on graph theory indicate that functional brain networks in schizophrenia are characterized by reduced small-worldness, lower degree connectivity of brain hubs, and decreased modularity. 6) Some of the alterations in functional connectivity observed in probands are present in unaffected relatives, raising the possibility that functional dysconnectivity is an endophenotype related to genetic risk for schizophrenia. Combined, these findings provide broad support for dysconnectivity theories of schizophrenia. We conclude our review with a discussion of the limitations of the existing literature and potentially important areas of future research.

Schizophrenia (SZ) is a severe neuropsychiatric disorder. A leading hypothesis is that SZ is a brain dysconnection syndrome, involving abnormal interactions between widespread brain networks. Resting state functional magnetic resonance imaging (R-fMRI) is a powerful tool to explore the dysconnectivity of brain networks in SZ and other disorders. Seed-based functional connectivity analysis, spatial independent component analysis (ICA), and graph theory-based analysis are popular methods to quantify brain network connectivity in R-fMRI data. Widespread network dysconnectivity in SZ has been observed using both seed-based analysis and ICA, although most seed-based studies report decreased connectivity while ICA studies report both increases and decreases. Importantly, most of the findings from both techniques are also associated with typical symptoms of the illness. Disrupted topological properties and altered modular community structure of brain system in SZ have been shown using graph theory-based analysis. Overall, the resting-state findings regarding brain networks deficits have advanced our understanding of the underlying pathology of SZ. In this article, we review aberrant brain connectivity networks in SZ measured in R-fMRI by the above approaches, and discuss future challenges.

Schizophrenia is a major mental illness that is characterized by psychosis, social withdrawal, and cognitive impairment. High comorbidity rates with substance use disorders have consistently been found – especially with abuse of cannabis and psychostimulants. While the role of these drugs in the onset of psychosis and schizophrenia has received much attention, relatively few studies have been conducted on the impact of psychoactive substances on the course of schizophrenia. In this review, study findings measuring the effects of psychoactive substances with structural and functional magnetic resonance imaging methods are described in patients suffering from substance use disorder and schizophrenia. Both Schizophrenia and substance abuse are associated with different functional brain alterations. In addicted individuals, drug-related cues and drug administration lead to increased neurofunctional activity in limbic and prefrontal brain regions compared to healthy controls. Chronic drug abuse is associated with gray matter loss in these areas. In schizophrenic patients, cognitive imaging in the frontal and temporal brain areas has showed decreased neural activity during the resting state. In chronic schizophrenic patients, the greatest loss of brain volume was found in those patients with additional substance abuse. Neuroimaging studies highlight the significance of regular drug use in schizophrenia. Whereas schizophrenic patients with and without substance abuse may not differ in structural imaging at the onset of illness, regular drug abuse seems to be a significant risk factor for severe loss of brain volume in the course of schizophrenia.

The hemispheres of the human brain are anatomically and functionally asymmetric. Many cognitive and motor functions such as language and handedness are lateralized. In this review, we discuss the principles of laterality and brain asymmetry in relation to schizophrenia. Schizophrenia is one of the most disabling forms of mental illness. One important challenge is to develop and set up biological markers, which can accurately identify at-risk individuals in preclinical stages and thus improve the effects of early intervention strategies. The concept of hemispheric laterality plays a central role in current neuropsychological and pathophysiological models of schizophrenia. Recent research reflects an increasing interest in the molecular and population genetics of laterality and its potential use as biological marker for the illness. The review is an overview of literature from the 1990's on cerebral asymmetry in schizophrenia. We critically discuss the use of cerebral asymmetry for biomarker research, regarding diagnosis improvements, the improvement of psychopharmacology and the prediction of conversion in at-risk individuals. We propose that abnormal cerebral asymmetry is an attractive biomarker candidate for schizophrenia that could index changes in a range of pathophysiological pathways.

At the most basic level, the Transcranial Magnetic Stimulation(TMS) is a neuro-scientific tool that exerts its action by influencing the neo-cortical functions. However, in-spite of so many well-evidenced roles of TMS in neuropsychiatric conditions, its exact mechanism of action remains to be known. More intriguing are its therapeutic effects in Schizophrenia at the Cerebral-level. In this review, we adopt a neuro-imaging approach for this exploration. We review the present literature for the studies in Schizophrenia which have used a combination of rTMS with 1) Electroenchephalogram (EEG) 2)The functional Magnetic Resonance Imaging (fMRI) and the 3) Positron Emission Tomography (PET)/ Single-Photon Emission Computed Tomography. The TMS-EEG combination provides direct effects of TMS on the electro- magnetic field (EMF) of brain. The TMS-fMRI/PET/SPECT combinations are very effective in exploring the functional connectivity in brains of Schizophrenia patients as well as in performing rTMS guided neuro-navigation. Our review suggests that TMS combined with other neuroimaging modalities are needed for a better clarification of its neural actions.