Widespread intra-axonal signal fraction abnormalities in bipolar disorder from multicompartment diffusion MRI: Sensitivity to diagnosis, association with clinical features and pharmacologic treatment.

Despite diffusion tensor imaging (DTI) evidence for widespread fractional anisotropy (FA) reductions in the brain white matter of patients with bipolar disorder, questions remain regarding the specificity and sensitivity of FA abnormalities as opposed to other diffusion metrics in the disorder. We conducted a whole-brain voxel-based multicompartment diffusion MRI study on 316 participants (i.e., 158 patients and 158 matched healthy controls) employing four diffusion metrics: the mean diffusivity (MD) and FA estimated from DTI, and the intra-axonal signal fraction (IASF) and microscopic axonal parallel diffusivity (Dpar) derived from the spherical mean technique. Our findings provide novel evidence about widespread abnormalities in other diffusion metrics in BD. An extensive overlap between the FA and IASF results suggests that the lower FA in patients may be caused by a reduced intra-axonal volume fraction or a higher macromolecular content in the intra-axonal water. We also found a diffuse alteration in MD involving white and grey matter tissue and more localised changes in Dpar. A Machine Learning analysis revealed that FA, followed by IASF, were the most helpful metric for the automatic diagnosis of BD patients, reaching an accuracy of 72%. Number of mood episodes, age of onset/duration of illness, psychotic symptoms, and current treatment with lithium, antipsychotics, antidepressants, and antiepileptics were all significantly associated with microstructure abnormalities. Lithium treatment was associated with less microstructure abnormality.

Do the negative symptoms of schizophrenia reflect reduced responsiveness to reward? Examination using a reward prediction error (RPE) task.

BACKGROUND: A leading theory of the negative symptoms of schizophrenia is that they reflect reduced responsiveness to rewarding stimuli. This proposal has been linked to abnormal (reduced) dopamine function in the disorder, because phasic release of dopamine is known to code for reward prediction error (RPE). Nevertheless, few functional imaging studies have examined if patients with negative symptoms show reduced RPE-associated activations. METHODS: Matched groups of DSM-5 schizophrenia patients with high negative symptom scores (HNS, N = 27) or absent negative symptoms (ANS, N = 27) and healthy controls (HC, N = 30) underwent fMRI scanning while they performed a probabilistic monetary reward task designed to generate a measure of RPE. RESULTS: In the HC, whole-brain analysis revealed that RPE was positively associated with activation in the ventral striatum, the putamen, and areas of the lateral prefrontal cortex and orbitofrontal cortex, among other regions. Group comparison revealed no activation differences between the healthy controls and the ANS patients. However, compared to the ANS patients, the HNS patients showed regions of significantly reduced activation in the left ventrolateral and dorsolateral prefrontal cortex, and in the right lingual and fusiform gyrus. HNS and ANS patients showed no activation differences in ventral striatal or midbrain regions-of-interest (ROIs), but the HNS patients showed reduced activation in a left orbitofrontal cortex ROI. CONCLUSIONS: The findings do not suggest that a generalized reduction of RPE signalling underlies negative symptoms. Instead, they point to a more circumscribed dysfunction in the lateral frontal and possibly the orbitofrontal cortex.

Neural correlates of referential/persecutory delusions in schizophrenia: examination using fMRI and a virtual reality underground travel paradigm.

BACKGROUND: The brain functional correlates of delusions have been relatively little studied. However, a virtual reality paradigm simulating travel on the London Underground has been found to evoke referential ideation in both healthy subjects and patients with schizophrenia, making brain activations in response to such experiences potentially identifiable. METHOD: Ninety patients with schizophrenia/schizoaffective disorder and 28 healthy controls underwent functional magnetic resonance imaging while they viewed virtual reality versions of full and empty Barcelona Metro carriages. RESULTS: Compared to the empty condition, viewing the full carriage was associated with activations in the visual cortex, the cuneus and precuneus/posterior cingulate cortex, the inferior parietal cortex, the angular gyrus and parts of the middle and superior temporal cortex including the temporoparietal junction bilaterally. There were no significant differences in activation between groups. Nor were there activations associated with referentiality or presence of delusions generally in the patient group. However, patients with persecutory delusions showed a cluster of reduced activation compared to those without delusions in a region in the right temporal/occipital cortex. CONCLUSIONS: Performance of the metro task is associated with a widespread pattern of activations, which does not distinguish schizophrenic patients and controls, or show an association with referentiality or delusions in general. However, the finding of a cluster of reduced activation close to the right temporoparietal junction in patients with persecutory delusions specifically is of potential interest, as this region is believed to play a role in social cognition.

Negative schizophrenic symptoms as prefrontal cortex dysfunction: Examination using a task measuring goal neglect.

BACKGROUND: The negative symptoms of schizophrenia have been proposed to reflect prefrontal cortex dysfunction. However, this proposal has not been consistently supported in functional imaging studies, which have also used executive tasks that may not capture key aspects of negative symptoms such as lack of volition. METHOD: Twenty-four DSM-5 schizophrenic patients with high negative symptoms (HNS), 25 with absent negative symptoms (ANS) and 30 healthy controls underwent fMRI during performance of the Computerized Multiple Elements Test (CMET), a task designed to measure poor organization of goal directed behaviour or 'goal neglect'. Negative symptoms were rated using the PANSS and the Clinical Assessment Interview for Negative Symptoms (CAINS). RESULTS: On whole brain analysis, the ANS patients showed no significant clusters of reduced activation compared to the healthy controls. In contrast, the HNS patients showed hypoactivation compared to the healthy controls in the left anterior frontal cortex, the right dorsolateral prefrontal cortex (DLPFC), the anterior insula bilaterally and the bilateral inferior parietal cortex. When compared to the ANS patients, the HNS patients showed reduced activation in the left anterior frontal cortex, the left DLPFC and the left inferior parietal cortex. After controlling for disorganization scores, differences remained in clusters in the left anterior frontal cortex and the bilateral inferior parietal cortex. CONCLUSIONS: This study provides evidence that reduced prefrontal activation, perhaps especially in the left anterior frontal cortex, is a brain functional correlate of negative symptoms in schizophrenia. The simultaneous finding of reduced inferior parietal cortex activation was unexpected, but could reflect this region's involvement in cognitive control, particularly the 'regulative' component of this.

Age- and gender-related differences in brain tissue microstructure revealed by multi-component T2 relaxometry.

In spite of extensive work, inconsistent findings and lack of specificity in most neuroimaging techniques used to examine age- and gender-related patterns in brain tissue microstructure indicate the need for additional research. Here, we performed the largest Multi-component T2 relaxometry cross-sectional study to date in healthy adults (N = 145, 18-60 years). Five quantitative microstructure parameters derived from various segments of the estimated T2 spectra were evaluated, allowing a more specific interpretation of results in terms of tissue microstructure. We found similar age-related myelin water fraction (MWF) patterns in men and women but we also observed differential male related results including increased MWF content in a few white matter tracts, a faster decline with age of the intra- and extra-cellular water fraction and its T2 relaxation time (i.e. steeper age related negative slopes) and a faster increase in the free and quasi-free water fraction, spanning the whole grey matter. Such results point to a sexual dimorphism in brain tissue microstructure and suggest a lesser vulnerability to age-related changes in women.

Brain imaging of executive function with the computerised multiple elements test.

The Computerised Multiple Elements Test (CMET) is a novel executive task to assess goal management and maintenance suitable for use within the fMRI environment. Unlike classical executive paradigms, it resembles neuropsychological multi-elements tests that capture goal management in a more ecological way, by requiring the participant to switch between four simple games within a specified time period. The present study aims to evaluate an fMRI version of the CMET and examine its brain correlates. Thirty-one healthy participants performed the task during fMRI scanning. During each block, they were required to play four simple games, with the transition between games being made either voluntarily (executive condition) or automatically (control condition). The executive condition was associated with increased activity in fronto-parietal and cingulo-opercular regions, with anterior insula activity linked to better task performance. In an additional analysis, the activated regions showed to form functional networks during resting-state and to overlap the executive fronto-parietal and cingulo-opercular networks identified in resting-state with independently defined seeds. These results show the ability of the CMET to elicit activity in well-known executive networks, becoming a potential tool for the study of executive impairment in neurological and neuropsychiatric populations in a more ecological way than classical paradigms.

Brain imaging correlates of self- and other-reflection in schizophrenia.

BACKGROUND: An alteration in self/other differentiation has been proposed as a basis for several symptoms in schizophrenia, including delusions of reference and social functioning deficits. Dysfunction of the right temporo-parietal junction (TPJ), a region linked with social cognition, has been proposed as the basis of this alteration. However, imaging studies of self- and other-processing in schizophrenia have shown, so far, inconsistent results. METHODS: Patients with schizophrenia and healthy controls underwent fMRI scanning while performing a task with three conditions: self-reflection, other-reflection and semantic processing. RESULTS: Both groups activated similar brain regions for self- and other-reflection compared to semantic processing, including the medial prefrontal cortex, the precuneus and the TPJ. Compared to healthy subjects, patients hyperactivated the left lateral frontal cortex during self- and other-reflection. In other-reflection, compared to self-reflection, patients failed to increase right TPJ activity. CONCLUSIONS: Altered activity in the right TPJ supports a disturbance in self/other differentiation in schizophrenia, which could be linked with psychotic symptoms and affect social functioning in patients. Hyperactivity of the lateral frontal cortex for self- and other-reflection suggests the presence of greater cognitive demand to perform the task in the patient group.

Shared and differential default-mode related patterns of activity in an autobiographical, a self-referential and an attentional task.

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.