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The experience of auditory verbal hallucinations (AVH, “hearing voices”) in schizophrenia has been found to be associated with reduced auditory cortex activation during perception of real auditory stimuli like tones and speech. We re-examined this finding using 46 patients with schizophrenia (23 with frequent AVH and 23 hallucination-free), who underwent fMRI scanning while they heard words, sentences and reversed speech. Twenty-five matched healthy controls were also examined. Perception of words, sentences and reversed speech all elicited activation of the bilateral superior temporal cortex, the inferior and lateral prefrontal cortex, the inferior parietal cortex and the supplementary motor area in the patients and the healthy controls. During the sentence and reversed speech conditions, the schizophrenia patients as a group showed reduced activation in the left primary auditory cortex (Heschl’s gyrus) relative to the healthy controls. No differences were found between the patients with and without hallucinations in any condition. This study therefore fails to support previous findings that experience of AVH attenuates speech-perception-related brain activations in the auditory cortex. At the same time, it suggests that schizophrenia patients, regardless of presence of AVH, show reduced activation in the primary auditory cortex during speech perception, a finding which could reflect an early information processing deficit in the disorder.

The default-mode network (DMN) comprises a set of brain regions that show deactivations during performance of attentionally demanding tasks, but also activation during certain processes including recall of autobiographical memories and processing information about oneself, among others. However, the DMN is not activated in a homogeneous manner during performance of such tasks, so it is not clear to what extent its activation patterns correspond to deactivation patterns seen during attention-demanding tasks. In this fMRI study we compared patterns of activation in response to an autobiographical memory task to those observed in a self/other-reflection task, and compared both to deactivations observed during the n-back working memory task. Autobiographical recall and self-reflection activated several common DMN areas, which were also deactivated below baseline levels by the n-back task. Activation in the medial temporal lobe was seen during autobiographical recall but not the self/other task, and right angular gyrus activity was specifically linked to other-reflection. ROI analysis showed that most, but not all DMN regions were activated above baseline levels during the autobiographical memory and self-reflection tasks. Our results provide evidence for the usefulness of the autobiographical memory task to study DMN activity and support the notion of interacting subsystems within this network.

Auditory verbal hallucinations (AVH, ‘hearing voices’) are an important symptom of schizophrenia but their biological basis is not well understood. One longstanding approach proposes that they are perceptual in nature, specifically that they reflect spontaneous abnormal neuronal activity in the auditory cortex, perhaps with additional ‘top down’ cognitive influences. Functional imaging studies employing the symptom capture technique—where activity when patients experience AVH is compared to times when they do not—have had mixed findings as to whether the auditory cortex is activated. Here, using a novel variant of the symptom capture technique, we show that the experience of AVH does not induce auditory cortex activation, even while real speech does, something that effectively rules out all theories that propose a perceptual component to AVH. Instead, we find that the experience of AVH activates language regions and/or regions that are engaged during verbal short-term memory.

Structural imaging studies of borderline personality disorder (BPD) have found regions of reduced cortical volume, but these have varied considerably across studies. Reduced hippocampus and amygdala volume have also been a regular finding in studies using conventional volumetric measurement. How far comorbid major depression, which is common in BPD and can also affect in brain structure, influences the findings is not clear. Seventy-six women with BPD and 76 matched controls were examined using whole-brain voxel-based morphometry (VBM). The hippocampus and amygdala were also measured, using both conventional volume measurement and VBM within a mask restricted to these two subcortical structures. Lifetime history of major depression was assessed using structured psychiatric interview. At a threshold of p = 0.05 corrected, the BPD patients showed clusters of volume reduction in the dorsolateral prefrontal cortex bilaterally and in the pregenual/subgenual medial frontal cortex. There was no evidence of volume reductions in the hippocampus or amygdala, either on conventional volumetry or using VBM masked to these regions. Instead there was evidence of right-sided enlargement of these structures. No significant structural differences were found between patients with and without lifetime major depression. According to this study, BPD is characterized by a restricted pattern of cortical volume reduction involving the dorsolateral frontal cortex and the medial frontal cortex, both areas of potential relevance for the clinical features of the disorder. Previous findings concerning reduced hippocampus and amygdala volume in the disorder are not supported. Brain structural findings in BPD do not appear to be explainable on the basis of history of associated lifetime major depression.

A disturbed sense of identity is one of the major features of borderline personality disorder (BPD), which manifests early in the course of the disorder, and is potentially examinable using functional imaging during tasks involving self-reflection. Twenty-seven medication-naïve adolescent female patients with BPD, who had no psychiatric comorbidities, and 28 matched healthy female controls underwent fMRI while answering questions either about themselves or acquaintances. Control conditions consisted of answering questions involving factual knowledge and a low-level baseline (cross fixation). When self-reflection was compared to fact processing, BPD patients exhibited reduced activation in the right dorsolateral prefrontal cortex (DLPFC), as well as in the left parietal and calcarine cortex and the right precuneus. In contrast, other-reflection was associated with relatively lower activation in the medial frontal cortex in BPD patients, with further analysis revealing that this change reflected a failure of de-activation during the fact processing condition. There were no differences between the BPD patients and controls when self- and other-processing was examined against low-level baseline. This study provides evidence of reduced DLPFC activation during self-reflection in adolescent females with BPD, which may reflect diminished top-down cognitive control of this process, but not other-reflection in the disorder.

The CACNA1C and the ZNF804A genes are among the most relevant schizophrenia GWAS findings. Recent evidence shows that the interaction of these genes with the schizophrenia diagnosis modulates brain functional response to a verbal fluency task. To better understand how these genes might influence the risk for schizophrenia, we aimed to study the interplay between CACNA1C and ZNF804A on working memory brain functional correlates. The analyses included functional and behavioural N-back task data (obtained from an fMRI protocol) and CACNA1C-rs1006737 and ZNF804A-rs1344706 genotypes for 78 healthy subjects and 78 patients with schizophrenia (matched for age, sex and premorbid IQ). We tested the effects of the epistasis between these genes as well as of the three-way interaction (CACNA1C × ZNAF804A × diagnosis) on working memory-associated activity (N-back: 2-back vs 1-back). We detected a significant CACNA1C × ZNAF804A interaction on working memory functional response in regions comprising the ventral caudate medially and within the left hemisphere, the superior and inferior orbitofrontal gyrus, the superior temporal pole and the ventral-anterior insula. The individuals with the GWAS-identified risk genotypes (CACNA1C-AA/AG and ZNF804A-AA) displayed a reduced working memory modulation response. This genotypic combination was also associated with opposite brain activity patterns between patients and controls. While further research will help to comprehend the neurobiological mechanisms of this interaction, our data highlight the role of the epistasis between CACNA1C and ZNF804A in the functional mechanisms underlying the pathophysiology of schizophrenia.

Regularization may be used as an alternative to dimensionality reduction when the number of variables in a model is much larger than the number of available observations. In a recent study from our group regularized regression was employed to quantify brain functional connectivity in a sample of healthy controls using a brain parcellation and resting state fMRI images. Here regularization is applied to evaluate resting state connectivity abnormalities at the voxel level in a sample of patients with schizophrenia Specifically, ridge regression is implemented with different degrees of regularization and results are compared to those delivered by the weighted global brain connectivity method (GBC), which is based on averaged bivariate correlations. Ridge regression is able to detect a much extended set of abnormally connected regions than the GBC, including schizophrenia related connectivity reductions in fronto-medial, somatosensory and occipital structures. Due to its multivariate nature, the proposed method is much more sensitive to group abnormalities than the GBC. Voxel based regularized regression is a simple and sensitive alternative for quantifying brain functional connectivity.

It has been suggested that the pathophysiology of panic disorder (PD) may involve abnormalities in several brain structures, including the amygdala. To date, however, no study has used quantitative structural neuroimaging techniques to examine amygdalar anatomy in this disorder. Volumetric magnetic resonance imaging (MRI) studies of the amygdalas, hippocampi, and temporal lobes were conducted in 12 drug-free, symptomatic PD patients (six females and six males), and 12 case-matched healthy comparison subjects. Volumetric MRI data were normalized for brain size. PD patients were found to have smaller left-sided and right-sided amygdalar volumes than controls. No differences were found in either hippocampi or temporal lobes. These findings provide new evidence of changes in amygdalar structure in PD and warrant further anatomical and MRI brain studies of patients with this disorder.

We sought to investigate the altered brain responses to emotional stimuli in patients with schizophrenia. We analyzed data from 14 patients with schizophrenia and 14 healthy controls who performed an emotional face matching task. We evaluated brain activity and connectivity in the amygdala and cortical regions during the initial (first 21seconds of each stimulation block) and sustained (last 21seconds) stages of an emotional processing task, and we determined changes in amygdala activity across the emotional processing task. The patients with schizophrenia showed similar amygdala activation to the controls during the initial stage of processing, but their activation decreased during the sustained stage. The controls showed increasing amygdala activity across the emotional blocks, whereas activity progressively decreased in the schizophrenia group. The patients with schizophrenia showed increased cortical activity and interconnectivity in the medial frontal and inferior parietal cortex in the initial stage of emotional processing. There was increased activity in the superior temporal cortex and greater connectivity with the inferior parietal cortex in the sustained stage. Performance accuracy was lower in the schizophrenia group in the first part of the block, while their reaction time was longer in the latter part of the block. It was not possible to specify the moment at which the switch in amygdala response occurred. Our findings suggest that patients with schizophrenia have an initial automatic emotional response but that they need to switch to a compensatory cognitive strategy to solve the task.