Resting-state glutamate level in the anterior cingulate predicts blood-oxygen level-dependent response to cognitive control.

The dorsal anterior cingulate cortex (dACC) is a core structure for the governing of cognitive control, and recent studies have shown that interindividual differences in dACC anatomy are associated with corresponding differences in the ability for cognitive control. However, individuals differ not only in anatomical features of dACC, but also exhibit substantial variability regarding the biochemical characteristics of the dACC. In this study, we combined magnetic resonance spectroscopy ((1)H-MRS) and functional magnetic resonance imaging (fMRI), finding that interindividual differences of glutamate levels in the dACC during resting-state predict the strength of the blood-oxygen level-dependent (BOLD) response to a task requiring cognitive control. This relationship was observed in the retrosplenial cortex, the orbitofrontal cortex, the inferior parietal lobe, and the basal ganglia. More specifically, individuals with low resting-state glutamate levels in the dACC showed an increased BOLD response when the task demands were high, whereas high-glutamate individuals showed the opposite pattern of an increased BOLD response when the task demands were low. Thus, we show here that individual variability of glutamate levels is directly related to how the brain implements cognitive control.

A critical re-examination of sexual dimorphism in the corpus callosum microstructure.

Recent diffusion-tensor imaging (DTI) studies suggest sexual dimorphism in the micro-structural architecture of the corpus callosum. However, the corpus callosum is also found to be larger in males than in females, a fact that might introduce a systematic bias to the analysis of DTI parameters. Diffusion parameters obtained in the larger male corpus callosum could be less affected by partial-volume averaging with surrounding non-callosal tissue than respective parameters obtained in the smaller female corpus callosum, i.e. the sex of the subject and partial-volume effects would be confounded. The objective of the present DTI study was to re-examine microstructural sex differences in the corpus callosum, while controlling for corpus callosum size differences between sexes. We compared 41 female and 34 male participants using regional tract-based spatial statistics (TBSS) analysis. Clusters of significantly higher fractional anisotropy (FA) and lower diffusion strength in males compared to females were detected in the genu and truncus of the corpus callosum. However, only the sex difference located in the anterior genu subregions could be unequivocally interpreted. This was the only cluster where the diffusion parameters did not correlate with regional callosal size. The present results indicate a stronger inter-hemispheric connectivity between the frontal lobes in males than females, which might be related to sex differences in hemispheric asymmetry and brain size.

Attention and cognitive control networks assessed in a dichotic listening fMRI study.

A meaningful interaction with our environment relies on the ability to focus on relevant sensory input and to ignore irrelevant information, i.e. top-down control and attention processes are employed to select from competing stimuli following internal goals. In this, the demands for the recruitment of top-down control processes depend on the relative perceptual salience of the competing stimuli. In the present functional magnetic resonance imaging (fMRI) study, we investigated the recruitment of top-down control processes in response to varying degrees of control demands in the auditory modality. For this purpose, we tested 20 male and 20 female subjects with a dichotic listening paradigm, in which the relative perceptual salience of two simultaneously presented stimuli was systematically manipulated by varying the inter-aural intensity difference (IID) and asking the subjects to selectively attend to either ear. The analysis showed that the interaction between IID and attentional direction involves two networks in the brain. A fronto-parietal network, including the pre-supplementary motor area, anterior cingulate cortex, inferior frontal junction, insula and inferior parietal lobe, was recruited during cognitively demanding conditions and can thus be seen as a top-down cognitive control network. In contrast, a second network including the superior temporal and the post-central gyri was engaged under conditions with low cognitive control demands. These findings demonstrate how cognitive control is achieved through the interplay of distinct brain networks, with their differential engagement determined as a function of the level of competition between the sensory stimuli.

Hallucinating schizophrenia patients have longer left arcuate fasciculus fiber tracks: a DTI tractography study.

The arcuate fasciculus (AF) has been implicated in the pathology behind schizophrenia and auditory verbal hallucinations (AVHs). White matter tracts forming the arcuate fasciculus can be quantified and visualized using diffusion tensor imaging (DTI) tractography. Although there have been a number of studies on this topic, the results have been conflicting. Studying the underlying white matter structure of the AF could shed light on the constrains for interaction between temporal and frontal language areas in AVHs. The participants were 66 patients with a schizophrenia diagnosis, where AVHs were defined from the Positive and Negative Syndrome Scale (PANSS), and compared with a healthy control group. DTI was performed on a 3T MR scanner, and tensor estimation was done using deterministic streamline tractography. Statistical analysis of the data showed significantly longer reconstructed tracks along the AF in patients with severe and frequent AVHs, as well as an overall significant asymmetry with longer tracks in the left compared to the right side. In addition, there were significant positive correlations between PANSS scores and track length, track volume, and number of track streamlines for the posterior AF segment on the left side. It is concluded that the present DTI results may have implications for interpretations of functional imaging results.

The Beliefs about Voices Questionnaire - Revised: A factor structure from 450 participants.

Hallucinated voices are common across psychiatric and non-clinical groups. The predominant cognitive theory about the impact of voices posits that beliefs about voice power ('Omnipotence') and voice intent ('Malevolence'/'Benevolence') play a key role in determining emotional and behavioral reactions. The revised Beliefs about Voices Questionnaire (BAVQ-R) was designed to assess these constructs, together with two styles of responding (Engagement and Resistance). The BAVQ-R is widely used in clinical and research settings, yet it has not received validation of its constructs and factor structure. This study examined the factor structure of the BAVQ-R by combining datasets from five study centers, comprising 450 participants (belief constructs) and 269 participants (response styles), and using confirmatory and exploratory factor analysis. Findings failed to support a three factor belief model, instead showing a two-factor structure ('Persecutory beliefs' combining Omnipotence and Malevolence constructs, and a Benevolent construct). Emotional and behavioral items did not separate. Overall, results showed that (i) a two-factor model of beliefs (Persecutory and Benevolent beliefs) provides a better fit to the data than a three-factor model, and (ii) emotional and behavioral modes of responding items should not be separated. Theoretical implications of this finding are discussed in relation to the research and therapy.

Impact of glutamate levels on neuronal response and cognitive abilities in schizophrenia.

Schizophrenia is characterized by impaired cognitive functioning, and brain regions involved in cognitive control processes show marked glutamatergic abnormalities. However, it is presently unclear whether aberrant neuronal response is directly related to the observed deficits at the metabolite level in schizophrenia. Here, 17 medicated schizophrenia patients and 17 matched healthy participants underwent functional magnetic resonance imaging (fMRI) when performing an auditory cognitive control task, as well as proton magnetic resonance spectroscopy ((1)H-MRS) in order to assess resting-state glutamate in the anterior cingulate cortex. The combined fMRI-(1)H-MRS analysis revealed that glutamate differentially predicted cortical blood-oxygen level-dependent (BOLD) response in patients and controls. While we found a positive correlation between glutamate and BOLD response bilaterally in the inferior parietal lobes in the patients, the corresponding correlation was negative in the healthy control participants. Further, glutamate levels predicted task performance in patients, such that lower glutamate levels were related to impaired cognitive control functioning. This was not seen for the healthy controls. These findings suggest that schizophrenia patients have a glutamate-related dysregulation of the brain network supporting cognitive control functioning. This could be targeted in future research on glutamatergic treatment of cognitive symptoms in schizophrenia.

Failure of attention focus and cognitive control in schizophrenia patients with auditory verbal hallucinations: evidence from dichotic listening.

Auditory verbal hallucinations (AVHs) are speech perceptions that lack an external source, phenomenologically experienced as "hearing voices". A perceptual origin of an AVH experience in patients with schizophrenia can however not explain why the "voices" drain the attentional and cognitive capacity of the patients, making them unable to direct attention away from the "voices" and to cognitively suppress the experience. We recently reported how AVHs interfere with the perception of speech sounds, using a dichotic listening experimental paradigm. We now extend this finding by reporting on the interference caused by AVHs on attention and cognitive control, using a slight variation of the same dichotic listening paradigm. The patients (N=148) were instructed to pay attention to and report from either the right or left ear syllable of the dichotic pair. We then correlated their PANSS score for the hallucination item (P3) with the performance score on the dichotic listening task. The results showed that AVHs interfered with the ability to report the right ear syllable when instructed to pay attention to the right side, which is a marker of inability to attend to an external speech stimulus. When instructed to pay attention to the left side, AVHs interfered with the ability to report the left ear syllable, which is a marker of inability to use cognitive control to suppress attending to the "voices". The corresponding correlations for the emotional withdrawal (N2) negative symptom were all non-significant. The correlations were substantiated in an ANOVA with corresponding significant group differences between high versus low symptom score groups. The results thus extend our previous findings of a perceptual origination for AVHs by showing that AVHs interfere with the ability to attend to the outer world around the patient, and the ability to inhibit, or suppress, the "voices" once they occur. Future research should pin down the neuronal basis of both the origination and the attentional and cognitive control aspects of AVHs.

The role of the primary auditory cortex in the neural mechanism of auditory verbal hallucinations.

Auditory verbal hallucinations (AVHs) are a subjective experience of "hearing voices" in the absence of corresponding physical stimulation in the environment. The most remarkable feature of AVHs is their perceptual quality, that is, the experience is subjectively often as vivid as hearing an actual voice, as opposed to mental imagery or auditory memories. This has lead to propositions that dysregulation of the primary auditory cortex (PAC) is a crucial component of the neural mechanism of AVHs. One possible mechanism by which the PAC could give rise to the experience of hallucinations is aberrant patterns of neuronal activity whereby the PAC is overly sensitive to activation arising from internal processing, while being less responsive to external stimulation. In this paper, we review recent research relevant to the role of the PAC in the generation of AVHs. We present new data from a functional magnetic resonance imaging (fMRI) study, examining the responsivity of the left and right PAC to parametrical modulation of the intensity of auditory verbal stimulation, and corresponding attentional top-down control in non-clinical participants with AVHs, and non-clinical participants with no AVHs. Non-clinical hallucinators showed reduced activation to speech sounds but intact attentional modulation in the right PAC. Additionally, we present data from a group of schizophrenia patients with AVHs, who do not show attentional modulation of left or right PAC. The context-appropriate modulation of the PAC may be a protective factor in non-clinical hallucinations.

Auditory verbal hallucinations in schizophrenia as aberrant lateralized speech perception: evidence from dichotic listening.

We report evidence that auditory verbal hallucinations (AVH) in schizophrenia patients are perceptual distortions lateralized to the left hemisphere. We used a dichotic listening task with repeated presentations of consonant-vowel syllables, a different syllable in the right and left ear. This task produces more correct reports for the right ear syllable in healthy individuals, indicative of left hemisphere speech processing focus. If AVHs are lateralized to the left hemisphere language receptive areas, then this should interfere with correct right ear reports in the dichotic task, which would result in significant negative correlations with severity of AVHs. We correlated the right and left ear correct reports with the PANSS hallucination symptom, and a randomly selected negative symptom, in addition to the sum total of the positive and negative symptoms, in 160 patients with schizophrenia. The results confirmed the predictions with significant negative correlations for the right ear scores with the PANSS hallucination item, and for the sum total of positive symptoms, while all other correlations were close to zero. The results are unambiguous evidence for AVHs as aberrant speech perceptions originating in the left hemisphere.