Gemma Modinos

A randomised pilot study to assess the efficacy of an interactive, multimedia tool of cognitive stimulation in Alzheimer's disease

Objective: To determine the usefulness of an interactive multimedia internet-based system (IMIS) for the cognitive stimulation of Alzheimer’s disease. Methods: This is a 24-week, single-blind, randomised pilot study conducted on 46 mildly impaired patients suspected of having Alzheimer’s disease receiving stable treatment with cholinesterase inhibitors (ChEIs). The patients were divided into three groups: (1) those who received 3 weekly, 20-min sessions of IMIS in addition to 8 h/day of an integrated psychostimulation program (IPP); (2) those who received only IPP sessions; and (3) those who received only ChEI treatment. The primary outcome measure was the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog). Secondary outcome measures were: Mini-Mental State Examination (MMSE), Syndrom Kurztest, Boston Naming Test, Verbal Fluency, and the Rivermead Behavioral Memory Test story recall subtest. Results: After 12 weeks, the patients treated with both IMIS and IPP had improved outcome scores on the ADAS-Cog and MMSE, which was maintained through 24 weeks of follow-up. The patients treated with IPP alone had better outcome than those treated with ChEIs alone, but the effects were attenuated after 24 weeks. All patients had improved scores in all of the IMIS individual tasks, attaining higher levels of difficulty in all cases. Conclusion: Although both the IPP and IMIS improved cognition in patients with Alzheimer’s disease, the IMIS program provided an improvement above and beyond that seen with IPP alone, which lasted for 24 weeks.

Neuroimaging Auditory Hallucinations in Schizophrenia: From Neuroanatomy to Neurochemistry and Beyond

Despite more than 2 decades of neuroimaging investigations, there is currently insufficient evidence to fully understand the neurobiological substrate of auditory hallucinations (AH). However, some progress has been made with imaging studies in patients with AH consistently reporting altered structure and function in speech and language, sensory, and nonsensory regions. This report provides an update of neuroimaging studies of AH with a particular emphasis on more recent anatomical, physiological, and neurochemical imaging studies. Specifically, we provide (1) a review of findings in schizophrenia and nonschizophrenia voice hearers, (2) a discussion regarding key issues that have interfered with progress, and (3) practical recommendations for future studies.

Individual differences in dispositional mindfulness and brain activity involved in reappraisal of emotion

The regulation of negative emotion through reappraisal has been shown to induce increased prefrontal activity and decreased amygdala activity. Individual differences in dispositional mindfulness reflect differences in typical recognition, detachment and regulation of current experience, thought to also operate as top-down control mechanism. We sought to investigate whether such individual differences would be associated with brain activity elicited during reappraisal of negative emotion. Eighteen healthy participants completed a functional magnetic resonance imaging task that involved attending to or reappraising negative stimuli, and provided emotion experience ratings after each trial. Dispositional mindfulness was assessed with a self-report questionnaire. Reappraisal induced activity in a brain network involving predominantly dorsal portions of the prefrontal cortex, replicating previous studies. A voxelwise regression analysis showed that individual differences in the tendency to be mindful predicted activity in neural regions underlying reappraisal, with dorsomedial prefrontal cortex activation increasing with more mindfulness traits. Notably, this prefrontal activation was inversely correlated with the amygdala response to negative scenes, further supporting its role in down-regulating emotion-generation regions. These findings suggest that individual differences in dispositional mindfulness, which reflect the tendency to recognize and regulate current states, may modulate activity in neural systems involved in the effective cognitive control of negative emotion.

Activation of Anterior Insula during Self-Reflection

Background Functional neuroimaging studies have suggested activation of midline frontoparietal brain regions to be at the core of self-related processes. However, although some studies reported involvement of the insula, little attention has been paid to this region as forming part of the “self”-network. Methodology/Principal Findings Using functional magnetic resonance imaging (fMRI), we aimed at replicating and extending previous studies by scanning subjects whilst reflecting upon their own personal qualities as compared to those of an acquaintance. A third condition with statements about general knowledge was used to control for attention, semantic processing and decision making processes. The results showed a significant effect of task in brain activity, consistent with previous findings, by which both person conditions recruited a common set of medial prefrontal and posterior regions, yet significant differences between self and other were found in the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC). Notably, significant neural activation in the left anterior insula was observed as uniquely associated with self-reflection. Conclusions/Significance The results provide further evidence for the specific recruitment of anterior MPFC and ACC regions for self-related processing, and highlight a role for the insula in self-reflection. As the insula is closely connected with ascending internal body signals, this may indicate that the accumulation of changes in affective states that might be implied in self-processing may contribute to our sense of self.

Neuroanatomy of auditory verbal hallucinations in schizophrenia : A quantitative meta-analysis of voxel-based morphometry studies

INTRODUCTION Voxel-based morphometry (VBM) studies demonstrate grey matter volume (GMV) deficits in schizophrenia. This method is also applied for detecting associations between specific psychotic symptoms and brain structure, such as auditory verbal hallucinations (AVHs). However, due to differing methodological approaches, the available findings are inconsistent and difficult to integrate. METHODS We used a novel voxel-based meta-analytical method to provide a robust quantitative review of neuroanatomical abnormalities specifically associated with the hallucinatory phenomenon in the schizophrenic brain. We reviewed all VBM studies of AVHs in schizophrenia published until July 2011 (n = 9). A total of 438 patients with a diagnosis of schizophrenia were included (307 with AVHs). Using a random-effects parametric voxel-based meta-analysis, coordinates of 83 foci reported as significant in the source studies were extracted and computed to estimate the brain locations most consistently associated with AVHs. RESULTS Severity of AVHs was significantly associated with GMV reductions in the left (p = .022) and marginally with the right (p = .062) superior temporal gyri (STGs, including Heschls gyri) across studies examining correlations with AVHs severity in patients (n = 8). Analysis of studies categorically comparing patients with and without AVHs did not reveal any significant findings, possibly due to the small number of studies using this approach (n = 3). CONCLUSIONS This meta-analysis implicates bilateral STG (including Heschls gyri) as key areas of structural pathology in AVHs in schizophrenia. These findings support a model postulating that aberrations within neural systems involved at different levels of language processing are critical to AVHs in schizophrenia.

Altered activation and functional connectivity of neural systems supporting cognitive control of emotion in psychosis proneness

Emotion regulation processes, such as reappraisal, are thought to operate through interactions between prefrontal emotion-control regions and subcortical emotion-generation regions such as the amygdala. Impairments in emotional processing and regulation have been reported in schizophrenia and at-risk populations. Psychometric measures may be used to detect vulnerability to schizophrenia in non-clinical samples, or psychosis proneness (PP). It has been shown that individuals with PP have a more than tenfold increased risk of developing a schizophrenia-spectrum disorder. In the present study, we used fMRI to examine the neural dynamics underlying reappraisal in such a sample. 600 undergraduate students completed the Community Assessment of Psychic Experiences Questionnaire (CAPE), positive subscale. Two groups were subsequently formed from the extremes of the distribution (total N=34). Blood-oxygenated-level-dependent activity elicited with a task involving 3 conditions was analyzed: viewing neutral pictures, viewing negative pictures, and reappraising negative pictures. Subjects reported the strength of experienced negative affect after each trial. Functional connectivity between prefrontal control regions and amygdala was investigated. At the behavioral level, both groups reported successful diminishment of experienced negative emotion. However, high psychosis-prone subjects showed stronger activation than low subjects in a number of prefrontal regions during reappraisal, relative to attending to negative pictures. The amygdala response to negative stimuli was decreased through reappraisal only in the low group. Functional connectivity analysis revealed less prefrontal-amygdala coupling in high psychosis-prone subjects. Thus, reduced cognitive control of emotion at a neural level appeared to be associated with PP. These findings extend the hypothesis of emotion dysregulation in schizophrenia to PP, and suggest that emotion regulation difficulties may be at the core of a vulnerability to psychosis.

Molecular genetic gene–environment studies using candidate genes in schizophrenia: A systematic review

The relatively high heritability of schizophrenia suggests that genetic factors play an important role in the etiology of the disorder. On the other hand, a number of environmental factors significantly influence its incidence. As few direct genetic effects have been demonstrated, and there is considerable inter-individual heterogeneity in the response to the known environmental factors, interactions between genetic and environmental factors may be important in determining whether an individual develops the disorder. To date, a considerable number of studies of gene-environment interactions (G×E) in schizophrenia have employed a hypothesis-based molecular genetic approach using candidate genes, which have led to a range of different findings. This systematic review aims to summarize the results from molecular genetic candidate studies and to review challenges and opportunities of this approach in psychosis research. Finally, we discuss the potential of future prospects, such as new studies that combine hypothesis-based molecular genetic candidate approaches with agnostic genome-wide association studies in determining schizophrenia risk.

Translating the MAM model of psychosis to humans

Elevated dopamine function and alterations in medial temporal lobe (MTL) structure and function are two of the most robust findings in schizophrenia, but how interactions between these abnormalities underlie the onset of psychosis is unclear. The methylazoxymethanol acetate (MAM) rodent model proposes that psychosis develops as a result of a perturbation of MTL function, leading to elevated striatal dopamine dysfunction. Here, we review several recent neuroimaging studies that examine components of the putative model in humans with an ultra high risk (UHR) of the psychosis. While data from these studies are broadly consistent with the MAM model, caution is required when comparing data across animal and human studies.

Schizotypy and brain structure: a voxel-based morphometry study

BACKGROUND Schizotypy is conceptualized as a subclinical manifestation of the same underlying biological factors that give rise to schizophrenia and other schizophrenia spectrum disorders. Individuals with psychometric schizotypy (PS) experience subthreshold psychotic signs and can be psychometrically identified among the general population. Previous research using magnetic resonance imaging (MRI) has shown gray-matter volume (GMV) abnormalities in chronic schizophrenia, in subjects with an at-risk mental state (ARMS) and in individuals with schizotypal personality disorder (SPD). However, to date, no studies have investigated the neuroanatomical correlates of PS. METHOD Six hundred first- and second-year university students completed the Community Assessment of Psychic Experiences (CAPE), a self-report instrument on psychosis proneness measuring attenuated positive psychotic experiences. A total of 38 subjects with high and low PS were identified and subsequently scanned with MRI. Voxel-based morphometry (VBM) was applied to examine GMV differences between subjects with high and low positive PS. RESULTS Subjects with high positive PS showed larger global volumes compared to subjects with low PS, and larger regional volumes in the medial posterior cingulate cortex (PCC) and the precuneus. There were no regions where GMV was greater in low than in high positive PS subjects. CONCLUSIONS These regions, the PCC and precuneus, have also been sites of volumetric differences in MRI studies of ARMS subjects and schizophrenia, suggesting that psychotic or psychotic-like experiences may have common neuroanatomical correlates across schizophrenia spectrum disorders.

Self-Reflection and the Psychosis-Prone Brain : An fMRI Study

OBJECTIVE The Cortical Midline Structures (CMS) play a critical role in self-reflection, together with the insula. Abnormalities in self-referential processing and its neural underpinnings have been reported in schizophrenia and at-risk populations, suggesting they might be markers of psychotic vulnerability. Psychometric measures of schizotypal traits may be used to index psychosis proneness (PP) in nonclinical samples. It remains an unresolved question whether differences in self-reflective processing are associated with PP. METHOD Six hundred students completed the Community Assessment of Psychic Experiences Questionnaire, positive subscale. Two groups were formed from the extremes of the distribution (total N = 36). fMRI was used to examine CMS/insula function during a self-reflection task. Participants judged personality trait sentences about self and about an acquaintance. RESULTS High PP subjects attributed less positive traits to others (i.e., acquaintances) than subjects with low PP. Across groups, the contrasts self > semantic and self > other induced activation in CMS and insula, whereas other > semantic did not produce insula activation. Other > self induced posterior cingulate cortex activation in low PP but not in high PP. In addition, high PP subjects showed stronger activation than low PP in left insula during self > semantic. Examining valence effects revealed that high PP individuals showed increased activation in left insula, right dMPFC, and left vMPFC for positive self-related traits, and in bilateral insula, ACC, and right dMPFC for negative self-related traits. CONCLUSIONS The findings suggest that aspects of self-referential processing and underlying brain mechanisms are similar in clinical and subclinical (high PP) forms of psychosis, suggesting that these may be associated with vulnerability to psychosis.