Social brain dysfunctions in schizophrenia: A review of neuroimaging studies

Several studies have indicated that schizophrenic patients show impaired performance in various aspects of social cognition, including theory of mind, emotion processing, and agency judgments. Neuroimaging studies that have compared patients and healthy subjects during such mental activity indicate an abnormal hemodynamic response in the medial prefrontal cortex, the prefrontal cortex, the amygdala, the inferior parietal lobe, i.e., a set of regions known to be critically involved in social cognition. This paper addresses a number of issues raised by schizophrenia research into theory of mind, emotion perception and self-agency with regards to the neural systems that mediate social cognition. In healthy subjects, typical brain patterns are associated with theory of mind, emotion perception and self-agency; some activated clusters overlap, while others are distinct. For instance, activations in the paracingulate gyrus are almost systematically associated with theory of mind tasks, while the amygdala is mainly involved in emotion perception tasks. Additional foci are frequently found activated during those tasks: superior temporal sulcus, inferior frontal area. Moreover, the inferior parietal lobe is thought to contribute to agency judgments. In the light of the data on brain abnormalities and neurochemical dysfunctions in schizophrenia, we discuss the interaction of social cognitive dysfunction with the supposed information processing abnormalities caused by dopamine dysregulation.     

Cortical brain development in schizophrenia: insights from neuroimaging studies in childhood-onset schizophrenia

Childhood-onset schizophrenia (COS; defined as onset by age 12 years) is rare, difficult to diagnose, and represents a severe and chronic phenotype of the adult-onset illness. A study of childhood-onset psychoses has been ongoing at the National Institute of Mental Health (NIMH) since 1990, where children with COS and severe atypical psychoses (provisionally labeled "multidimensionally impaired" or MDI by the NIMH team) are studied prospectively along with all first-degree relatives. COS subjects have robust cortical gray matter (GM) loss during adolescence, which appears to be an exaggeration of the normal cortical GM developmental pattern and eventually mimics the pattern seen in adult-onset cases as the children become young adults. These cortical GM changes in COS are diagnostically specific and seemingly unrelated to the effects of medications. Furthermore, the cortical GM loss is also shared by healthy full siblings of COS probands suggesting a genetic influence on the abnormal brain development.     

Typical and atypical brain development: a review of neuroimaging studies

In the course of development, the brain undergoes a remarkable process of restructuring as it adapts to the environment and becomes more efficient in processing information. A variety of brain imaging methods can be used to probe how anatomy, connectivity, and function change in the developing brain. Here we review recent discoveries regarding these brain changes in both typically developing individuals and individuals with neurodevelopmental disorders. We begin with typical development, summarizing research on changes in regional brain volume and tissue density, cortical thickness, white matter integrity, and functional connectivity. Space limits preclude the coverage of all neurodevelopmental disorders; instead, we cover a representative selection of studies examining neural correlates of autism, attention deficit/hyperactivity disorder, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Down syndrome, and Turner syndrome. Where possible, we focus on studies that identify an age by diagnosis interaction, suggesting an altered developmental trajectory. The studies we review generally cover the developmental period from infancy to early adulthood. Great progress has been made over the last 20 years in mapping how the brain matures with MR technology. With ever-improving technology, we expect this progress to accelerate, offering a deeper understanding of brain development, and more effective interventions for neurodevelopmental disorders.     

Sex steroids and connectivity in the human brain: a review of neuroimaging studies

Our brain operates by the way of interconnected networks. Connections between brain regions have been extensively studied at a functional and structural level, and impaired connectivity has been postulated as an important pathophysiological mechanism underlying several neuropsychiatric disorders. Yet the neurobiological mechanisms contributing to the development of functional and structural brain connections remain to be poorly understood. Interestingly, animal research has convincingly shown that sex steroid hormones (estrogens, progesterone and testosterone) are critically involved in myelination, forming the basis of white matter connectivity in the central nervous system. To get insights, we reviewed studies into the relation between sex steroid hormones, white matter and functional connectivity in the human brain, measured with neuroimaging. Results suggest that sex hormones organize structural connections, and activate the brain areas they connect. These processes could underlie a better integration of structural and functional communication between brain regions with age. Specifically, ovarian hormones (estradiol and progesterone) may enhance both cortico-cortical and subcortico-cortical functional connectivity, whereas androgens (testosterone) may decrease subcortico-cortical functional connectivity but increase functional connectivity between subcortical brain areas. Therefore, when examining healthy brain development and aging or when investigating possible biological mechanisms of 'brain connectivity' diseases, the contribution of sex steroids should not be ignored.     

The hallucinating brain: a review of structural and functional neuroimaging studies of hallucinations

Hallucinations remains one of the most intriguing phenomena in psychopathology. In the past two decades the advent of neuroimaging techniques have allowed researchers to investigate what is happening in the brain of those who experience hallucinations. In this article we review both structural and functional neuroimaging studies of patients with auditory and visual hallucinations as well as a small number of studies that have assessed cognitive processes associated with hallucinations in healthy volunteers. The current literature suggests that in addition to secondary (and occasionally primary) sensory cortices, dysfunction in prefrontal premotor, cingulate, subcortical and cerebellar regions also seem to contribute to hallucinatory experiences. Based on the findings of these studies we tentatively propose a neurocognitive model in which both bottom-up and top-down processes interact to produce these erroneous percepts. Finally, directions for future work are discussed.     

Structural neuroimaging studies in late-life depression: a review.

Which patients presenting with depression in late life will progress to a dementia syndrome has been an important research question in recent times. In this paper we review selectively structural neuroimaging investigations of late-life depression (LLD) that have been performed over the past two decades. These studies indicate that there are neuroimaging changes commonly observed in LLD patients when compared to normal controls. Findings include ventricular enlargement and sulcal widening, and reduction in volume size of frontal lobes, hippocampus and caudate nucleus. White matter lesions are more common in depressed subjects and tend to be more severe. Some studies report these changes to be more pronounced in patients who present with late-onset depression (LOD) but this has been contradicted by other studies. Preliminary work suggests that these changes may be associated with a poor prognosis but there is a dearth of systematic, well-controlled longitudinal studies.     

Face recognition in schizophrenia disorder: A comprehensive review of behavioral,neuroimaging and neurophysiological studies

Facial emotion processing has been extensively studied in schizophrenia patients while general face processing has received less attention. The already published reviews do not address the current scientific literature in a complete manner. Therefore, here we tried to answer some questions that remain to be clarified, particularly: are the non-emotional aspects of facial processing in fact impaired in schizophrenia patients? At the behavioral level, our key conclusions are that visual perception deficit in schizophrenia patients: are not specific to faces; are most often present when the cognitive (e.g. attention) and perceptual demands of the tasks are important; and seems to worsen with the illness chronification. Although, currently evidence suggests impaired second order configural processing, more studies are necessary to determine whether or not holistic processing is impaired in schizophrenia patients. Neural and neurophysiological evidence suggests impaired earlier levels of visual processing, which might involve the deficits in interaction of the magnocellular and parvocellular pathways impacting on further processing. These deficits seem to be present even before the disorder out-set. Although evidence suggests that this deficit may be not specific to faces, further evidence on this question is necessary, in particularly more ecological studies including context and body processing.     

The suicidal mind and brain: A review of neuropsychological and neuroimaging studies

Abstract

Objectives. We aimed at reviewing studies exploring dysfunctional cognitive processes, and their neuroanatomical basis, in suicidal behaviour, and to develop a neurocognitive working model. Methods. A literature search was conducted. Results. Several limitations were found. The main reported neuropsychological findings are a higher attention to specific negative emotional stimuli, impaired decision-making, lower problem-solving abilities, reduced verbal fluency, and possible reduced non-specific attention and reversal learning in suicide attempters. Neuroimaging studies mainly showed the involvement of ventrolateral orbital, dorsomedial and dorsolateral prefrontal cortices, the anterior cingulate gyrus, and, to a lesser extent, the amygdala. In addition, alterations in white matter connections are suggested. Conclusions. These studies support the concept of alterations in suicidal behaviour distinct from those of comorbid disorders. We propose that a series of neurocognitive dysfunctions, some with trait-like characteristics, may facilitate the development of a suicidal crisis during stressful circumstances: (1) an altered modulation of value attribution, (2) an inadequate regulation of emotional and cognitive responses, and (3) a facilitation of acts in an emotional context. This preliminary model may represent a framework for the design of future studies on the pathophysiology, prediction and prevention of these complex human behaviours.     

Mapping prodromal psychosis: a critical review of neuroimaging studies

The onset of schizophrenia is usually preceded by a prodromal phase characterized by functional decline and subtle prodromal symptoms, which include attenuated psychotic phenomena, cognitive deterioration and a decline in socio-occupational function. Preventive interventions during this phase are of great interest because of the impressive clinical benefits. However, available psychopathological criteria employed to define a high risk state for psychosis have low validity and specificity. Consequently there is an urgent need of reliable neurocognitive markers linked to the pathophysiological mechanisms that underlie schizophrenia. Neuroimaging techniques have rapidly developed into a powerful tool in psychiatry as they provide an unprecedented opportunity for the investigation of brain structure and function. This review shows that neuroimaging studies of the prodromal phases of psychosis have the potentials to identify core structural and functional markers of an impending risk to psychosis and to clarify the dynamic changes underlying transition to psychosis and to address significant correlations between brain structure or function and prodromal psychopathology. Additionally, neurochemical methods can address the key role played by neurotransmitters such as dopamine and glutamate during the psychosis onset. To conclude, multimodal neuroimaging may ultimately clarify the neurobiology of the prodromal phases by the integration of functional, structural and neurochemical findings.     

Behavioral and neuroimaging studies on schizophrenia in Japan

Abstracts Chronic methamphetamine psychotics became a major problem in Japan after World War II. On one hand, the clinical symptoms of chronic methamphetamine psychotics were noted to resemble those of schizophrenics quite closely but, on the other hand, their respective personality profiles appeared to differ. Recent research on exploratory eye movements has also shown such similarities and differences. In long-term remitted chronic methamphetamine psychotics, extremely small doses of drugs, or stress, can be enough to cause a recurrence of symptoms. This phenomenon resembles the recurrence of schizophrenia, and animal experiments and basic research are being actively conducted in order to elucidate the mechanism involved.
Some 20 years ago, unique studies were conducted that objectively looked at the characteristic behavior of severe chronic schizophrenics in a playground situation. Exploratory eye movements can also be regarded as a kind of behavior and, in this paper, eye movement patterns made in response to a maze test are discussed. In addition, much research on brain imaging in schizophrenia is being conducted in Japan and several interesting studies have also been chosen by the authors for presentation in this paper.     

Endophenotypes in schizophrenia: a review of electrophysiological studies

Schizophrenia patients consistently show some deficiency in electrophysiological measures, such as PPI (Prepulse Inhibition), ERP (Event-Related Potential) components (mismatch negativity, P50, P300), EEG (Electroencephalography), and MEG (Magnetoencephalography). These components have been intensively studied as quantitative biological markers (i.e., endophenotypes) for psychiatric disorders. Recently brain oscillations, especially gamma (30-80 Hz) band activity (GBA), are being increasingly investigated as new candidate endophenotypes. In this review, we summarize the current status, perspective, and limitations of representative paradigms for investigating abnormal electrophysiological components of schizophrenia, along with relevant genetic polymorphism.     

Neuropathological studies of schizophrenia: a selective review

Over the past 20 years, there has been a relatively quiet but persistent effort to investigate anatomical neuropathology in schizophrenia. This effort has involved post-mortem histopathology using novel preparation procedures, pneumoencephalography, and computed tomography. The bulk of this research is critically reviewed here. The evidence presented suggests that the brains of schizophrenic patients frequently contain abnormalities. The limbic region is especially likely to show pathological changes. However, the changes are variable and nonspecific. The implications of these findings are discussed in terms of our limited knowledge of the clinical manifestations of subtle limbic pathology. It is concluded that pathology of limbic regions is associated with schizophrenia and that the more gross the pathology, the more neurologically impaired are the patients.     

Age of onset of schizophrenia: perspectives from structural neuroimaging studies

Many of the major neuropsychiatric illnesses, including schizophrenia, have a typical age of onset in late adolescence. Late adolescence may reflect a critical period in brain development making it particularly vulnerable for the onset of psychopathology. Neuroimaging studies that focus on this age range may provide unique insights into the onset and course of psychosis. In this review, we examine the evidence from 2 unique longitudinal cohorts that span the ages from early childhood through young adulthood; a study of childhood-onset schizophrenia where patients and siblings are followed from ages 6 through to their early twenties, and an ultra-high risk study where subjects (mean age of 19 years) are studied before and after the onset of psychosis. From the available evidence, we make an argument that subtle, regionally specific, and genetically influenced alterations during developmental age windows influence the course of psychosis and the resultant brain phenotype. The importance of examining trajectories of development and the need for future combined approaches, using multimodal imaging together with molecular studies is discussed.     

Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia

Although there is considerable evidence that patients with schizophrenia fail to activate the dorsolateral prefrontal cortex (DLPFC) to the degree seen in normal comparison subjects when performing working memory or executive tasks, hypofrontality may be coupled with relatively increased activity in other brain regions. However, most imaging studies of working memory in schizophrenia have focused on DLPFC activity. The goal of this work is to review functional neuroimaging studies that contrasted patients with schizophrenia and healthy comparison subjects during a prototypical working memory task, the n-back paradigm, to highlight areas of hyper- and hypoactivation in schizophrenia. We utilize a quantitative meta-analysis method to review 12 imaging studies where patients with schizophrenia were contrasted with healthy comparison subjects while performing the n-back paradigm. Although we find clear support for hypofrontality, we also document consistently increased activation in anterior cingulate and left frontal pole regions in patients with schizophrenia compared to that in controls. These data suggest that whereas reduced DLPFC activation is reported consistently in patients with schizophrenia relative to healthy subjects, abnormal activation patterns are not restricted to this region, raising questions as to whether the pathophysiological dysfunction in schizophrenia is specific to the DLPFC and about the relationship between impaired performance and aberrant activation patterns. The complex pattern of hyper- and hypoactivation consistently found across studies implies that rather than focusing on DLPFC dysregulation, researchers should consider the entire network of regions involved in a given task when making inferences about the biological mechanisms of schizophrenia.     

Executive dysfunctions in schizophrenia

Abstract. Studies suggest that executive functions in patients with schizophrenia are markedly impaired as compared with normal controls. Most previous studies employed tests of executive functions adopted from frontal lobe neuropsychological paradigms based on lesion studies. This study employed several more recently developed theory–driven tests of executive functions addressing the construct of the supervisory attentional system. We explore the pattern of executive function impairment using factor analysis and subsequently investigate the relationships between these executive function factors and the clinical features in a sample of chronic schizophrenic patients. A total of 51 patients with chronic schizophrenia were recruited. The Sustained Attention Response to Task (SART), Six Elements Test (SET) and Hayling Sentence Completion Test (HSC) were used to assess executive functions. Three factors were identified within the executive function tests: 1) The semantic inhibition factor comprised items in the HSC, 2) the action/attention inhibition factor comprised the SART commission error and the SET rulebreaking score and 3) the output generation factor comprised the SET raw score and the correct SART response. Significant relationships were found between these derived factors and clinical features after partialling out the confounding effect of age, education and illness duration. The three theory–based tests of executive function were shown to have good construct validity among the group of chronic schizophrenic patients.Part of the findings were presented at the 11^th Biennial Winter Workshop on Schizophrenia at Davos, Switzerland, 24 February–1 March 2002     

Retinal dysfunctions in schizophrenia

The purpose of this study was to investigate the earliest stages of visual information processing using electroretinography (ERG) in patients with schizophrenia and bipolar disorder and to compare these values with those of healthy control volunteers. In the acute stage of the illness, patients with schizophrenia exhibited decreased a-wave amplitude (a measure of photoreceptor function) as compared with healthy controls. In patients with bipolar disorder, ERG measures were intact. At the baseline assessment, there was a significant negative relationship between a-wave amplitude and positive symptoms. After an 8-week follow-up period, clinical symptoms showed significant improvement and the amplitude of the a-wave significantly increased in patients with schizophrenia. At the follow-up assessment, there was no significant difference between patients with schizophrenia and controls. These results indicate that retinal dysfunctions are specific for schizophrenia, as compared with bipolar disorder, and are confined to the acute stage of the illness.     

Amygdala recruitment in schizophrenia in response to aversive emotional material: a meta-analysis of neuroimaging studies

Emotional dysfunction has long been established as a critical clinical feature of schizophrenia. In the past decade, there has been extensive work examining the potential contribution of abnormal amygdala activation to this dysfunction in patients with schizophrenia. A number of studies have demonstrated under-recruitment of the amygdala in response to emotional stimuli, while others have shown intact recruitment of this region. To date, there have been few attempts to synthesize this literature using quantitative criteria or to use a formal meta-analytic approach to examine which variables may moderate the magnitude of between-group differences in amygdala activation in response to aversive emotional stimuli. We conducted a meta-analysis of amygdala activation in patients with schizophrenia, using a bootstrapping approach to investigate: (a) evidence for amygdala under-recruitment in schizophrenia and (b) variables that may moderate the magnitude of between-group differences in amygdala activation. We demonstrate that patients with schizophrenia show statistically significant, but modest, under-recruitment of bilateral amygdala (mean effect size = -0.20 SD). However, present findings indicate that this under-recruitment is dependent on the use of a neutral vs emotion interaction contrast and is not apparent if amygdala activation by patients and controls is evaluated in a negative emotional condition only.