Sukhwinder Shergill

Age Effects on Diffusion Tensor Magnetic Resonance Imaging Tractography Measures of Frontal Cortex Connections in Schizophrenia

Diffusion tensor magnetic resonance imaging (DT‐MRI) has previously been used to investigate white matter tracts in schizophrenia, with inconsistent results. The aim of the study was to use a novel method for tract‐specific measurements of fronto‐temporal fasciculi in early‐onset schizophrenia. We hypothesized that by making tract‐specific measurements, clear diffusion abnormalities would be revealed in specific fasciculi in schizophrenia. Measurements of diffusion anisotropy and mean diffusivity were localized within fronto‐temporal fasciculi by forming 3‐D reconstructions of the cingulum, uncinate, superior longitudinal, and inferior fronto‐occipital fasciculi using diffusion tensor tractography. We were limited in our ability to test our hypothesis by the important and surprising finding that age affected DT‐MRI‐based measures in schizophrenia patients in a different way from comparison subjects, most notably in the left superior longitudinal fasciculus. The youngest schizophrenia patients that we studied had lower diffusion anisotropy than age‐matched comparison subjects, but this difference diminished with increasing age. The main conclusion of this study was that direct comparisons of absolute DT‐MRI‐based measures between individuals with schizophrenia and comparison subjects may be problematic and misleading because of underlying age‐related differences in brain maturation between groups. Hum Brain Mapp, 2005.

Auditory hallucinations: a review of psychological treatments

Auditory hallucinations (AH) occur frequently amongst psychiatric patients, being most common in schizophrenia. In 25-30% of cases they are refractory to traditional antipsychotic drugs. A variety of psychosocial treatments have been used, but their efficacy remains unclear. This review aims to bring together the more recent studies of psychological treatments and discuss them in the context of recent cognitive models of hallucinations and functional imaging studies. The search strategy included the following sources: MEDLINE, Embase and Psychlit. Strategies reported by patients can be categorised as: (1) distracting activities, such as listening to music; (2) behavioural tasks, such as taking exercise; (3) cognitive tasks, such as ignoring AH. Almost all the strategies produced some benefit in some patients: treatment often improved AH-associated distress, rather than frequency of AH. There are many difficulties in conducting research on AH. Treatment should be individually tailored and used as an adjunct to pharmacotherapy. Future theory-driven studies need to be based on complex aetiological models and incorporate functional imaging to elucidate the physiological changes induced by therapeutic interventions.

Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials

OBJECTIVES Existing treatments for schizophrenia can improve positive symptoms, but it is unclear if they have any impact on negative symptoms. This meta-analysis was conducted to assess the efficacy of available treatments for negative symptoms in schizophrenia. METHODS All randomized-controlled trials of interventions for negative symptoms in schizophrenia until December 2013 were retrieved; 168 unique and independent placebo-controlled trials were used. Negative symptom scores at baseline and follow-up, duration of illness, doses of medication, type of interventions, and sample demographics were extracted. Heterogeneity was addressed with the I (2) and Q statistic. Standardized mean difference in values of the Negative Symptom Rating Scale used in each study was calculated as the main outcome measure. RESULTS 6503 patients in the treatment arm and 5815 patients in the placebo arm were included. No evidence of publication biases found. Most treatments reduced negative symptoms at follow-up relative to placebo: second-generation antipsychotics: -0.579 (-0.755 to -0.404); antidepressants: -0.349 (-0.551 to -0.146); combinations of pharmacological agents: -0.518 (-0.757 to -0.279); glutamatergic medications: -0.289 (-0.478 to -0.1); psychological interventions: -0.396 (-0.563 to -0.229). No significant effect was found for first-generation antipsychotics: -0.531 (-1.104 to 0.041) and brain stimulation: -0.228 (-0.775 to 0.319). Effects of most treatments were not clinically meaningful as measured on Clinical Global Impression Severity Scale. CONCLUSIONS AND RELEVANCE Although some statistically significant effects on negative symptoms were evident, none reached the threshold for clinically significant improvement.

Modulation of activity in temporal cortex during generation of inner speech.

Monitoring ones thoughts (in the verbal modality) is thought to be critically dependent on the interaction between areas that generate and perceive inner speech in the frontal and temporal cortex, respectively. We used functional magnetic resonance imaging (fMRI) to examine the relationship between activity in these areas while the rate of inner speech generation was varied experimentally. The faster rate was associated with activation in the left inferior frontal gyrus, the right pre‐ and postcentral gyri and both superior temporal gyri. Thus, temporal cortical activation was associated with increasing the rate of covert articulation, in the absence of external auditory input, suggesting that there is effective fronto‐temporal connectivity. Furthermore, this may provide support for the existence of feed forward models, which suggest that activity in regions responsible for verbal perception is modulated by activity in areas that generate inner speech. Hum. Brain Mapping 16:219–227, 2002.

White matter microstructure in schizophrenia: effects of disorder, duration and medication

Background Diffusion tensor magnetic resonance imaging studies in schizophrenia to date have been largely inconsistent. This may reflect variation in methodology, and the use of small samples with differing illness duration and medication exposure. Aims To determine the extent and location of white matter microstructural changes in schizophrenia, using optimised diffusion tensor imaging in a large patient sample, and to consider the effects of illness duration and medication exposure. Method Scans from 76 patients with schizophrenia and 76 matched controls were used to compare fractional anisotropy, a measure of white matter microstructural integrity, between the groups. Results We found widespread clusters of reduced fractional anisotropy in patients, affecting most major white matter tracts. These reductions did not correlate with illness duration, and there was no difference between age-matched chronically and briefly medicated patients. Conclusions The finding of widespread fractional anisotropy reductions in our larger sample of patients with schizophrenia may explain some of the inconsistent findings of previous, smaller studies.

Altered Integrity of Perisylvian Language Pathways in Schizophrenia: Relationship to Auditory Hallucinations

BACKGROUND Functional neuroimaging supports the hypothesis that auditory verbal hallucinations (AVH) in schizophrenia result from altered functional connectivity between perisylvian language regions, although the extent to which AVH are also associated with an altered tract anatomy is less clear. METHODS Twenty-eight patients with schizophrenia subdivided into 17 subjects with a history of AVH and 11 without a history of hallucinations and 59 age- and IQ-matched healthy controls were recruited. The number of streamlines, fractional anisotropy (FA), and mean diffusivity were measured along the length of the arcuate fasciculus and its medial and lateral components. RESULTS Patients with schizophrenia had bilateral reduction of FA relative to controls in the arcuate fasciculi (p < .001). Virtual dissection of the subcomponents of the arcuate fasciculi revealed that these reductions were specific to connections between posterior temporal and anterior regions in the inferior frontal and parietal lobe. Also, compared with controls, the reduction in FA of these tracts was highest, and bilateral, in patients with AVH, but in patients without AVH, this reduction was reported only on the left. CONCLUSIONS These findings point toward a supraregional network model of AVH in schizophrenia. They support the hypothesis that there may be selective vulnerability of specific anatomical connections to posterior temporal regions in schizophrenia and that extensive bilateral damage is associated with a greater vulnerability to AVH. If confirmed by further studies, these findings may advance our understanding of the anatomical factors that are protective against AVH and predictive of a treatment response.

Oxytocin decreases aversion to angry faces in an associative learning task.

Social and financial considerations are often integrated when real life decisions are made, and recent studies have provided evidence that similar brain networks are engaged when either social or financial information is integrated. Other studies, however, have suggested that the neuropeptide oxytocin can specifically affect social behaviors, which would suggest separable mechanisms at the pharmacological level. Thus, we examined the hypothesis that oxytocin would specifically affect social and not financial information in a decision making task, in which participants learned which of the two faces, one smiling and the other angry or sad, was most often being rewarded. We found that oxytocin specifically decreased aversion to angry faces, without affecting integration of positive or negative financial feedback or choices related to happy vs sad faces.

A Diffusion Tensor Magnetic Resonance Imaging Study of Frontal Cortex Connections in Very-Late-Onset Schizophrenia-Like Psychosis

OBJECTIVE Onset of psychosis after the age of 60 may be associated with structural abnormalities within cerebral white matter. The authors looked within white-matter tracts, which mediate connectivity of the frontal lobes, in psychotic patients for evidence of loss of fiber integrity consistent with degenerative damage. METHODS Fourteen patients with very-late-onset schizophrenia-like psychosis and an age-matched control group underwent diffusion tensor magnetic resonance imaging. Tract maps were constructed for each subject from the imaging data, and measurements of fractional anisotropy and mean diffusivity were made within the uncinate, superior longitudinal, and inferior occipito-frontal fasciculi, and the cingulum. RESULTS There were no significant differences in fractional anisotropy, a measure of the ordering of axons within fiber tracts, nor in mean diffusivity, an orientationally-averaged measure of the bulk diffusivity within each voxel, between patients and control subjects. CONCLUSION The lack of difference in fractional anisotropy and mean diffusivity measures between patients and controls argues against the presence of structural abnormalities within these tracts and the notion that a focal white-matter abnormality within the tracts investigated underpins the onset of psychosis.

Functional magnetic resonance imaging of inner speech in schizophrenia

BACKGROUND Auditory verbal hallucinations in schizophrenia have been linked to defective monitoring of ones own verbal thoughts. Previous studies have shown that patients with auditory verbal hallucinations show attenuated activation of brain regions involved with auditory processing during the monitoring of inner speech. However, there are no functional magnetic resonance imaging studies explicitly comparing the perception of external speech with internal speech in the same patients with schizophrenia. The present study investigated the functional neuroanatomy of inner and external speech in both patients with schizophrenia and healthy control subjects. METHODS Fifteen patients with schizophrenia and 12 healthy control subjects were studied using functional magnetic resonance imaging while listening to sentences or imagining sentences. RESULTS Significant interactions between group (control subjects vs. patients) and task (listening vs. inner speech) were seen for the left superior temporal gyrus, as well as regions within the cingulate gyrus. CONCLUSIONS Attenuated deactivation of the left superior temporal gyrus in schizophrenia patients during the processing of inner speech may reflect deficits in the forward models subserving self-monitoring.

Gender Differences in White Matter Microstructure

Background Sexual dimorphism in human brain structure is well recognised, but little is known about gender differences in white matter microstructure. We used diffusion tensor imaging to explore differences in fractional anisotropy (FA), an index of microstructural integrity. Methods A whole brain analysis of 135 matched subjects (90 men and 45 women) using a 1.5 T scanner. A region of interest (ROI) analysis was used to confirm those results where proximity to CSF raised the possibility of partial-volume artefact. Results Men had higher fractional anisotropy (FA) in cerebellar white matter and in the left superior longitudinal fasciculus; women had higher FA in the corpus callosum, confirmed by ROI. Discussion The size of the differences was substantial - of the same order as that attributed to some pathology – suggesting gender may be a potentially significant confound in unbalanced clinical studies. There are several previous reports of difference in the corpus callosum, though they disagree on the direction of difference; our findings in the cerebellum and the superior longitudinal fasciculus have not previously been noted. The higher FA in women may reflect greater efficiency of a smaller corpus callosum. The relatively increased superior longitudinal fasciculus and cerebellar FA in men may reflect their increased language lateralisation and enhanced motor development, respectively.