Stefania Benetti

Functional integration between the posterior hippocampus and prefrontal cortex is impaired in both first episode schizophrenia and the at risk mental state

Recent neuroimaging studies have reported deficits in functional integration between prefrontal cortex and the hippocampal formation in schizophrenia. It is unclear whether these alterations are a consequence of chronic illness or its treatment, and whether they are also evident in non-psychotic subjects at increased risk of the disorder. We addressed these issues by investigating prefrontal-hippocampal interactions in patients with first episode schizophrenia and subjects with an At Risk Mental State (ARMS). Using functional Magnetic Resonance Imaging, we measured brain responses from 16 individuals with an ARMS, 10 patients with first episode schizophrenia and 14 healthy controls during a delayed matching to sample task. Dynamic causal modelling was used to estimate the effective connectivity between prefrontal cortex and anterior and posterior hippocampal regions. The normal pattern of effective connectivity from the right posterior hippocampus to the right inferior frontal gyrus was significantly decreased in both first episode patients and subjects with an ARMS (ANOVA; F = 8.16, P = 0.01). Interactions between the inferior frontal gyrus and the anterior part of the hippocampus did not differ across the three groups. Perturbed hippocampal-prefrontal interactions are evident in individuals at high risk of developing psychosis and in patients who have just developed schizophrenia. This suggests that it may be a correlate of increased vulnerability to psychosis and that it is not attributable to an effect of chronic illness or its treatment.

Effects of stressful life events on human brain structure: a longitudinal voxel-based morphometry study.

Although stressful life events (SLEs) have been associated with an increased risk of illness and mental disorder, their impact on brain anatomy remains poorly understood. Using a longitudinal design, we tested the hypothesis that SLEs are significantly associated with changes in gray matter volume (GMV) in brain regions previously implicated in post-traumatic stress disorder (PTSD) in a group of clinically healthy adults. Magnetic resonance imaging was used to acquire an anatomical scan from 26 subjects (13 males and 13 females; mean age ± SD: 25.2 ± 4.3 years), with no psychiatric diagnosis, at two time points with a 3-month interval. Voxel-based morphometry was used to examine an association between SLEs and gray matter changes during this period. The number of SLEs was associated with a decrease in GMV in the anterior cingulate, hippocampus, and parahippocampal gyrus (p < 0.001). In contrast, there were no areas where the number of SLEs was associated with an increase in GMV. These results provide evidence that, in adults with no formal psychiatric diagnosis, SLEs are associated with GMV decreases in a subset of regions implicated in PTSD, and that these alterations can be observed within a period as short as 3 months.

The effects of psychotherapy on brain function: A systematic and critical review

Over the past two decades, the development of neuroimaging techniques has allowed the non-invasive investigation of neuroplastic changes associated with psychotherapeutic treatment. The aim of the present article is to present a systematic and critical review of longitudinal studies addressing the impact of psychotherapy on the brain published to date. After summarizing the results reported in the literature for each psychiatric disorder separately (i.e. obsessive-compulsive disorder, panic disorder, unipolar major depressive disorder, posttraumatic stress disorder, specific phobia, schizophrenia), we discuss the results focusing on three questions of interest: (i) whether neurobiological changes which follow psychotherapy occur in regions that showed significant neurofunctional alteration pre-treatment; (ii) whether these neurobiological changes are similar, or different, to those observed following pharmacological treatment; and (iii) whether neurobiological changes could be used as an objective means of monitoring the progress and outcome of psychotherapy. The evidence reviewed indicates that (i) depending on the disorder under investigation, psychotherapy results in either a normalisation of abnormal patterns of activity, the recruitment of additional areas which did not show altered activation prior to treatment, or a combination of the two; (ii) the effects of psychotherapy on brain function are comparable to those of medication for some but not all disorders; and (iii) there is preliminary evidence that neurobiological changes are associated with the progress and outcome of psychotherapy. It is hoped that a better understanding of the impact of psychotherapy on brain function will eventually inform the development of new biologically informed treatments and allow clinicians to make more effective treatment decisions.

Using genetic, cognitive and multi-modal neuroimaging data to identify ultra-high-risk and first-episode psychosis at the individual level

Background Group-level results suggest that relative to healthy controls (HCs), ultra-high-risk (UHR) and first-episode psychosis (FEP) subjects show alterations in neuroanatomy, neurofunction and cognition that may be mediated genetically. It is unclear, however, whether these groups can be differentiated at single-subject level, for instance using the machine learning analysis support vector machine (SVM). Here, we used a multimodal approach to examine the ability of structural magnetic resonance imaging (sMRI), functional MRI (fMRI), diffusion tensor neuroimaging (DTI), genetic and cognitive data to differentiate between UHR, FEP and HC subjects at the single-subject level using SVM. Method Three age- and gender-matched SVM paired comparison groups were created comprising 19, 19 and 15 subject pairs for FEP versus HC, UHR versus HC and FEP versus UHR, respectively. Genetic, sMRI, DTI, fMRI and cognitive data were obtained for each participant and the ability of each to discriminate subjects at the individual level in conjunction with SVM was tested. Results Successful classification accuracies (p < 0.05) comprised FEP versus HC (genotype, 67.86%; DTI, 65.79%; fMRI, 65.79% and 68.42%; cognitive data, 73.69%), UHR versus HC (sMRI, 68.42%; DTI, 65.79%), and FEP versus UHR (sMRI, 76.67%; fMRI, 73.33%; cognitive data, 66.67%). Conclusions The results suggest that FEP subjects are identifiable at the individual level using a range of biological and cognitive measures. Comparatively, only sMRI and DTI allowed discrimination of UHR from HC subjects. For the first time FEP and UHR subjects have been shown to be directly differentiable at the single-subject level using cognitive, sMRI and fMRI data. Preliminarily, the results support clinical development of SVM to help inform identification of FEP and UHR subjects, though future work is needed to provide enhanced levels of accuracy.

Auditory verbal hallucinations and brain dysconnectivity in the perisylvian language network: A multimodal investigation

Neuroimaging studies of schizophrenia have indicated that the development of auditory verbal hallucinations (AVHs) is associated with altered structural and functional connectivity within the perisylvian language network. However, these studies focussed mainly on either structural or functional alterations in patients with chronic schizophrenia. Therefore, they were unable to examine the relationship between the 2 types of measures and could not establish whether the observed alterations would be expressed in the early stage of the illness. We used diffusion tensor imaging and functional magnetic resonance imaging to examine white matter integrity and functional connectivity within the left perisylvian language network of 46 individuals with an at risk mental state for psychosis or a first episode of the illness, including 28 who had developed AVH group and 18 who had not (nonauditory verbal hallucination [nAVH] group), and 22 healthy controls. Inferences were made at P < .05 (corrected). The nAVH group relative to healthy controls showed a reduction of both white matter integrity and functional connectivity as well as a disruption of the normal structure−function relationship along the fronto-temporal pathway. For all measures, the AVH group showed intermediate values between healthy controls and the nAVH group. These findings seem to suggest that, in the early stage of the disorder, a significant impairment of fronto-temporal connectivity is evident in patients who do not experience AVHs. This is consistent with the hypothesis that, whilst mild disruption of connectivity might still enable the emergence of AVHs, more severe alterations may prevent the occurrence of the hallucinatory experience.

Attachment style, affective loss and gray matter volume: A voxel-based morphometry study

Early patterns of infant attachment have been shown to be an important influence on adult social behavior. Animal studies suggest that patterns of early attachment influence brain development, contributing to permanent alterations in neural structure; however, there are no previous studies investigating whether differences in attachment style are associated with differences in brain structure in humans. In this study, we used Magnetic Resonance Imaging (MRI) and voxel‐based morphometry (VBM) to examine for the first time the association between attachment style, affective loss (for example, death of a loved one) and gray matter volume in a healthy sample of adults (n = 32). Attachment style was assessed on two dimensions (anxious and avoidant) using the ECR‐Revised questionnaire. High attachment‐related anxiety was associated with decreased gray matter in the anterior temporal pole and increased gray matter in the left lateral orbital gyrus. A greater number of affective losses was associated with increased gray matter volume in the cerebellum; in this region, however, the impact of affective losses was significantly moderated by the level of attachment‐related avoidance. These findings indicate that differences in attachment style are associated with differences in the neural structure of regions implicated in emotion regulation. It is hypothesized that early attachment experience may contribute to structural brain differences associated with attachment style in adulthood; furthermore, these findings point to a neuronal mechanism through which attachment style may mediate individual differences in responses to affective loss. Hum Brain Mapp, 2010.

An empirical comparison of different approaches for combining multimodal neuroimaging data with support vector machine.

In the pursuit of clinical utility, neuroimaging researchers of psychiatric and neurological illness are increasingly using analyses, such as support vector machine, that allow inference at the single-subject level. Recent studies employing single-modality data, however, suggest that classification accuracies must be improved for such utility to be realized. One possible solution is to integrate different data types to provide a single combined output classification; either by generating a single decision function based on an integrated kernel matrix, or, by creating an ensemble of multiple single modality classifiers and integrating their predictions. Here, we describe four integrative approaches: (1) an un-weighted sum of kernels, (2) multi-kernel learning, (3) prediction averaging, and (4) majority voting, and compare their ability to enhance classification accuracy relative to the best single-modality classification accuracy. We achieve this by integrating structural, functional, and diffusion tensor magnetic resonance imaging data, in order to compare ultra-high risk (n = 19), first episode psychosis (n = 19) and healthy control subjects (n = 23). Our results show that (i) whilst integration can enhance classification accuracy by up to 13%, the frequency of such instances may be limited, (ii) where classification can be enhanced, simple methods may yield greater increases relative to more computationally complex alternatives, and, (iii) the potential for classification enhancement is highly influenced by the specific diagnostic comparison under consideration. In conclusion, our findings suggest that for moderately sized clinical neuroimaging datasets, combining different imaging modalities in a data-driven manner is no “magic bullet” for increasing classification accuracy. However, it remains possible that this conclusion is dependent on the use of neuroimaging modalities that had little, or no, complementary information to offer one another, and that the integration of more diverse types of data would have produced greater classification enhancement. We suggest that future studies ideally examine a greater variety of data types (e.g., genetic, cognitive, and neuroimaging) in order to identify the data types and combinations optimally suited to the classification of early stage psychosis.

Elucidating neuroanatomical alterations in the at risk mental state and first episode psychosis: A combined voxel-based morphometry and voxel-based cortical thickness study

Previous studies have reported alterations in grey matter volume and cortical thickness in individuals at high risk of developing psychosis and patients in the early stages of the disorder. Because these studies have typically focused on either grey matter volume or cortical thickness separately, the relationship between these two types of alterations is currently unclear. In the present investigation we used both voxel-based cortical thickness (VBCT) and voxel-based morphometry (VBM) to examine neuroanatomical differences in 21 individuals with an At Risk Mental State (ARMS) for psychosis, 26 patients with a First Episode of Psychosis (FEP) and 24 healthy controls. Statistical inferences were made at P < 0.05 after correction for multiple comparisons. Cortical thinning in the right superior temporal gyrus was observed in both individuals at high risk of developing psychosis and patients with a first episode of the disorder, and therefore is likely to represent a marker of vulnerability. In contrast, the right posterior cingulate cortex showed cortical thinning in FEP patients relative to individuals at high risk, and therefore appears to be implicated in the onset of the disease. These neuroanatomical differences were expressed in terms of cortical thickness but not in terms of grey matter volume, and therefore may reflect specific cortical atrophy as opposed to variations in sulcal and gyral morphology.

Attentional Modulation of Source Attribution in First-Episode Psychosis: A Functional Magnetic Resonance Imaging Study

BACKGROUND In patients with schizophrenia, the misattribution of self-generated events to an external source is associated with the presence of psychotic symptoms. The aim of this study was to investigate how this misattribution is influenced by dysfunction of attentional processing, which is also impaired in schizophrenia. METHODS Participants underwent functional Magnetic Resonance Imaging (fMRI) while listening to prerecorded speech. Their expectancies were manipulated using visual cues that were either congruent (valid) or incongruent (invalid) with the speech. The source (self/other) and the acoustic quality (undistorted/distorted) of the speech were also manipulated. Twenty patients with first-episode psychosis (FEP) and 20 matched healthy controls (HC) were tested. RESULTS When listening to self-generated speech preceded by an invalid (other speech) cue, relative to HC, FEP patients showed a trend to misidentify their own speech as that of another person. Analysis of fMRI data showed that FEP patients had reduced activation in the right middle temporal gyrus (MTG) and left precuneus (Pc) relative to HC. Within the FEP group, the level of activation in the right MTG was negatively correlated with the severity of their positive psychotic symptoms. CONCLUSIONS Impaired attentional modulation in schizophrenia may contribute to the tendency for FEP patients to misattribute the source of self-generated material, and this may be mediated by the right MTG and Pc, regions that are involved in both self-referential processing and the integration of sensory information.

Clinical utility of magnetic resonance imaging in first-episode psychosis

BackgroundThere is no consensus as to whether magnetic resonance imaging (MRI) should be used as part of the initial clinical evaluation of patients with first-episode psychosis (FEP).Aims(a) To assess the logistical feasibility of routine MRI; (b) to define the clinical significance of radiological abnormalities in patients with FEP.MethodRadiological reports from MRI scans of two FEP samples were reviewed; one comprised 108 patients and 98 healthy controls recruited to a research study and the other comprised 241 patients scanned at initial clinical presentation plus 66 healthy controls.ResultsIn the great majority of patients, MRI was logistically feasible. Radiological abnormalities were reported in 6% of the research sample and in 15% of the clinical sample (odds ratio (OR)=3.1, 95% CI 1.26-7.57, χ2(1) = 6.63, P = 0.01). None of the findings necessitated a change in clinical management.ConclusionsRates of neuroradiological abnormalities in FEP are likely to be underestimated in research samples that often exclude patients with organic abnormalities. However, the majority of findings do not require intervention.