Sukhi Shergill

Acoustic Noise and Functional Magnetic Resonance Imaging: Current Strategies and Future Prospects

Functional magnetic resonance imaging (fMRI) has become the method of choice for studying the neural correlates of cognitive tasks. Nevertheless, the scanner produces acoustic noise during the image acquisition process, which is a problem in the study of auditory pathway and language generally. The scanner acoustic noise not only produces activation in brain regions involved in auditory processing, but also interferes with the stimulus presentation. Several strategies can be used to address this problem, including modifications of hardware and software. Although reduction of the source of the acoustic noise would be ideal, substantial hardware modifications to the current base of installed MRI systems would be required. Therefore, the most common strategy employed to minimize the problem involves software modifications. In this work we consider three main types of acquisitions: compressed, partially silent, and silent. For each implementation, paradigms using block and event‐related designs are assessed. We also provide new data, using a silent event‐related (SER) design, which demonstrate higher blood oxygen level‐dependent (BOLD) response to a simple auditory cue when compared to a conventional image acquisition. J. Magn. Reson. Imaging 2002;16:497–510.

Modality specific neural correlates of auditory and somatic hallucinations

Somatic hallucinations occur in schizophrenia and other psychotic disorders, although auditory hallucinations are more common. Although the neural correlates of auditory hallucinations have been described in several neuroimaging studies, little is known of the pathophysiology of somatic hallucinations. Functional magnetic resonance imaging (fMRI) was used to compare the distribution of brain activity during somatic and auditory verbal hallucinations, occurring at different times in a 36 year old man with schizophrenia. Somatic hallucinations were associated with activation in the primary somatosensory and posterior parietal cortex, areas that normally mediate tactile perception. Auditory hallucinations were associated with activation in the middle and superior temporal cortex, areas involved in processing external speech. Hallucinations in a given modality seem to involve areas that normally process sensory information in that modality.

Dysconnectivity of neurocognitive networks at rest in very-preterm born adults.

Advances in neonatal medicine have resulted in a larger proportion of preterm-born individuals reaching adulthood. Their increased liability to psychiatric illness and impairments of cognition and behaviour intimate lasting cerebral consequences; however, the central physiological disturbances remain unclear. Of fundamental importance to efficient brain function is the coordination and contextually-relevant recruitment of neural networks. Large-scale distributed networks emerge perinatally and increase in hierarchical complexity through development. Preterm-born individuals exhibit systematic reductions in correlation strength within these networks during infancy. Here, we investigate resting-state functional connectivity in functional magnetic resonance imaging data from 29 very-preterm (VPT)-born adults and 23 term-born controls. Neurocognitive networks were identified with spatial independent component analysis conducted using the Infomax algorithm and employing Icasso procedures to enhance component robustness. Network spatial focus and spectral power were not generally significantly affected by preterm birth. By contrast, Granger-causality analysis of the time courses of network activity revealed widespread reductions in between-network connectivity in the preterm group, particularly along paths including salience-network features. The potential clinical relevance of these Granger-causal measurements was suggested by linear discriminant analysis of topological representations of connection strength, which classified individuals by group with a maximal accuracy of 86%. Functional connections from the striatal salience network to the posterior default mode network informed this classification most powerfully. In the VPT-born group it was additionally found that perinatal factors significantly moderated the relationship between executive function (which was reduced in the VPT-born as compared with the term-born group) and generalised partial directed coherence. Together these findings show that resting-state functional connectivity of preterm-born individuals remains compromised in adulthood; and present consistent evidence that the striatal salience network is preferentially affected. Therapeutic practices directed at strengthening within-network cohesion and fine-tuning between-network inter-relations may have the potential to mitigate the cognitive, behavioural and psychiatric repercussions of preterm birth.

Gender Influence on White Matter Microstructure: A Tract-Based Spatial Statistics Analysis

Background Sexual dimorphism in human brain structure is well recognised, but less is known about gender differences in white matter microstructure. We used diffusion tensor imaging to explore gender differences in fractional anisotropy (FA), an index of microstructural integrity. We previously found increased FA in the corpus callosum in women, and increased FA in the cerebellum and left superior longitudinal fasciculus (SLF) in men, using a whole-brain voxel-based analysis. Methods A whole-brain tract-based spatial statistics analysis of 120 matched subjects from the previous analysis, and 134 new subjects (147 men and 107 women in total) using a 1.5T scanner, with division into tract-based regions of interest. Results Men had higher FA in the superior cerebellar peduncles and women had higher FA in corpus callosum in both the first and second samples. The higher SLF FA in men was not found in either sample. Discussion We confirmed our previous, controversial finding of increased FA in the corpus callosum in women, and increased cerebellar FA in men. The corpus callosum FA difference offers some explanation for the otherwise puzzling advantage in inter-callosal transfer time shown in women; the cerebellar FA difference may be associated with the developmental motor advantage shown in men.

Performance on a probabilistic inference task in healthy subjects receiving ketamine compared with patients with schizophrenia

Evidence suggests that some aspects of schizophrenia can be induced in healthy volunteers through acute administration of the non-competitive NMDA-receptor antagonist, ketamine. In probabilistic inference tasks, patients with schizophrenia have been shown to ‘jump to conclusions’ (JTC) when asked to make a decision. We aimed to test whether healthy participants receiving ketamine would adopt a JTC response pattern resembling that of patients. The paradigmatic task used to investigate JTC has been the ‘urn’ task, where participants are shown a sequence of beads drawn from one of two ‘urns’, each containing coloured beads in different proportions. Participants make a decision when they think they know the urn from which beads are being drawn. We compared performance on the urn task between controls receiving acute ketamine or placebo with that of patients with schizophrenia and another group of controls matched to the patient group. Patients were shown to exhibit a JTC response pattern relative to their matched controls, whereas JTC was not evident in controls receiving ketamine relative to placebo. Ketamine does not appear to promote JTC in healthy controls, suggesting that ketamine does not affect probabilistic inferences.

Uncertainty and confidence from the triple-network perspective: Voxel-based meta-analyses

Our subjective confidence about particular events is related to but independent from the objective certainty of the stimuli we encounter. Surprisingly, previous investigations of the neurophysiological correlates of confidence and uncertainty have largely been carried out separately. After systematically reviewing the blood oxygenation-level dependent functional magnetic resonance imaging (BOLD fMRI) literature, and splitting studies on the basis of their task requirements, a voxel-based meta-analysis was performed to identify: (i) those regions which are replicably modulated by the uncertainty of environmental conditions; (ii) those regions whose activity is robustly affected by our subjective confidence; and (iii) those regions differentially activated at these contrasting times. In further meta-analyses the consistency of activation between these judgement types was assessed. Increased activation was consistently observed in the salience (anterior cingulate cortex and insula) and central executive network (dorsolateral prefrontal and posterior parietal cortices) in conditions of increased uncertainty; by contrast, default mode network (midline cortical and medial temporal lobe) regions robustly exhibited a positive relationship with subjective confidence. Regions including right parahippocampal gyrus were positively modulated by magnitude across both certainty and confidence judgements. This region was also shown to be more significantly modulated by confidence magnitude as compared with degree of environmental certainty. The functional and methodological implications of these findings are discussed with a view to improving future investigation of the neural basis of metacognitive judgement.

Do you see what I see? Sex differences in the discrimination of facial emotions during adolescence

During adolescence social relationships become increasingly important. Establishing and maintaining these relationships requires understanding of emotional stimuli, such as facial emotions. A failure to adequately interpret emotional facial expressions has previously been associated with various mental disorders that emerge during adolescence. The current study examined sex differences in emotional face processing during adolescence. Participants were adolescents (n = 1951) with a target age of 14, who completed a forced-choice emotion discrimination task. The stimuli used comprised morphed faces that contained a blend of two emotions in varying intensities (11 stimuli per set of emotions). Adolescent girls showed faster and more sensitive perception of facial emotions than boys. However, both adolescent boys and girls were most sensitive to variations in emotion intensity in faces combining happiness and sadness, and least sensitive to changes in faces comprising fear and anger. Furthermore, both sexes overidentified happiness and anger. However, the overidentification of happiness was stronger in boys. These findings were not influenced by individual differences in the level of pubertal maturation. These results indicate that male and female adolescents differ in their ability to identify emotions in morphed faces containing emotional blends. The findings provide information for clinical studies examining whether sex differences in emotional processing are related to sex differences in the prevalence of psychiatric disorders within this age group.

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder

Genome‐wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium‐channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract‐based spatial statistics and threshold‐free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ‐specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.

White matter changes in treatment refractory schizophrenia: Does cognitive control and myelination matter?

Widespread white matter abnormalities have been reported in schizophrenia, a disorder frequently characterised as a dysconnection syndrome. White matter connectivity in schizophrenia has been predominantly investigated using diffusion weighted imaging, with reductions in fractional anisotropy throughout the brain often interpreted as an indicator of abnormal myelination. However, diffusion weighted imaging lacks specificity and as such a number of microstructural factors besides myelin may be contributing to these results. We utilised multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) in medicated patients with chronic schizophrenia, stratified by treatment response status, and healthy controls, in order to assess myelin water fraction (MWF) in these groups. In addition, we assessed cognitive control using the Stroop task to investigate how response inhibition relates to myelination in patients and controls. Both treatment resistant (n = 22) and treatment responsive (n = 21) patients showed reduced MWF compared to healthy controls (n = 24) in bilateral fronto-occipital fasciculi, particularly evident in the vicinity of the striatum und extending to the cerebellum, with no difference between patient groups. Patients showed greater reaction time interference on the Stroop task compared to healthy controls, with no difference between patient groups. Stroop interference was significantly negatively correlated with MWF in the corpus callosum across groups, and MWF differences in this region mediated the behavioural group effects on the Stroop task. These findings support the suitability of mcDESPOT as a myelin-specific measure of abnormal connectivity in schizophrenia, and suggest that treatment resistant schizophrenia is not characterised by more severe abnormalities in myelination or cognitive control compared to treatment responsive schizophrenia.

Stimulating thought: a functional MRI study of transcranial direct current stimulation in schizophrenia

&NA; Individuals with schizophrenia typically suffer a range of cognitive deficits, including prominent deficits in working memory and executive function. These difficulties are strongly predictive of functional outcomes, but there is a paucity of effective therapeutic interventions targeting these deficits. Transcranial direct current stimulation is a novel neuromodulatory technique with emerging evidence of potential pro‐cognitive effects; however, there is limited understanding of its mechanism. This was a double‐blind randomized sham controlled pilot study of transcranial direct current stimulation on a working memory (n‐back) and executive function (Stroop) task in 28 individuals with schizophrenia using functional magnetic resonance imaging. Study participants received 30 min of real or sham transcranial direct current stimulation applied to the left frontal cortex. The ‘real’ and ‘sham’ groups did not differ in online working memory task performance, but the transcranial direct current stimulation group demonstrated significant improvement in performance at 24 h post‐transcranial direct current stimulation. Transcranial direct current stimulation was associated with increased activation in the medial frontal cortex beneath the anode; showing a positive correlation with consolidated working memory performance 24 h post‐stimulation. There was reduced activation in the left cerebellum in the transcranial direct current stimulation group, with no change in the middle frontal gyrus or parietal cortices. Improved performance on the executive function task was associated with reduced activity in the anterior cingulate cortex. Transcranial direct current stimulation modulated functional activation in local task‐related regions, and in more distal nodes in the network. Transcranial direct current stimulation offers a potential novel approach to altering frontal cortical activity and exerting pro‐cognitive effects in schizophrenia.