Paul Klauser

Reduced orbitofrontal cortical thickness in male adolescents with internet addiction

BackgroundThe orbitofrontal cortex (OFC) has consistently been implicated in the pathology of both drug and behavioral addictions. However, no study to date has examined OFC thickness in internet addiction. In the current study, we investigated the existence of differences in cortical thickness of the OFC in adolescents with internet addiction. On the basis of recently proposed theoretical models of addiction, we predicted a reduction of thickness in the OFC of internet addicted individuals.FindingsParticipants were 15 male adolescents diagnosed as having internet addiction and 15 male healthy comparison subjects. Brain magnetic resonance images were acquired on a 3T MRI and group differences in cortical thickness were analyzed using FreeSurfer. Our results confirmed that male adolescents with internet addiction have significantly decreased cortical thickness in the right lateral OFC (p<0.05).ConclusionThis finding supports the view that the OFC alterations in adolescents with internet addiction reflect a shared neurobiological marker of addiction-related disorders in general.

Lack of Evidence for Regional Brain Volume or Cortical Thickness Abnormalities in Youths at Clinical High Risk for Psychosis: Findings From the Longitudinal Youth at Risk Study

There is cumulative evidence that young people in an at-risk mental state (ARMS) for psychosis show structural brain abnormalities in frontolimbic areas, comparable to, but less extensive than those reported in established schizophrenia. However, most available data come from ARMS samples from Australia, Europe, and North America while large studies from other populations are missing. We conducted a structural brain magnetic resonance imaging study from a relatively large sample of 69 ARMS individuals and 32 matched healthy controls (HC) recruited from Singapore as part of the Longitudinal Youth At-Risk Study (LYRIKS). We used 2 complementary approaches: a voxel-based morphometry and a surface-based morphometry analysis to extract regional gray and white matter volumes (GMV and WMV) and cortical thickness (CT). At the whole-brain level, we did not find any statistically significant difference between ARMS and HC groups concerning total GMV and WMV or regional GMV, WMV, and CT. The additional comparison of 2 regions of interest, hippocampal, and ventricular volumes, did not return any significant difference either. Several characteristics of the LYRIKS sample like Asian origins or the absence of current illicit drug use could explain, alone or in conjunction, the negative findings and suggest that there may be no dramatic volumetric or CT abnormalities in ARMS.

White Matter Disruptions in Schizophrenia Are Spatially Widespread and Topologically Converge on Brain Network Hubs

White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brains fiber bundles.

Accelerated Gray and White Matter Deterioration With Age in Schizophrenia

OBJECTIVEnAlthough brain changes in schizophrenia have been proposed to mirror those found with advancing age, the trajectory of gray matter and white matter changes during the disease course remains unclear. The authors sought to measure whether these changes in individuals with schizophrenia remain stable, are accelerated, or are diminished with age.nnnMETHODnGray matter volume and fractional anisotropy were mapped in 326 individuals diagnosed with schizophrenia or schizoaffective disorder and in 197 healthy comparison subjects aged 20-65 years. Polynomial regression was used to model the influence of age on gray matter volume and fractional anisotropy at a whole-brain and voxel level. Between-group differences in gray matter volume and fractional anisotropy were regionally localized across the lifespan using permutation testing and cluster-based inference.nnnRESULTSnSignificant loss of gray matter volume was evident in schizophrenia, progressively worsening with age to a maximal loss of 8% in the seventh decade of life. The inferred rate of gray matter volume loss was significantly accelerated in schizophrenia up to middle age and plateaued thereafter. In contrast, significant reductions in fractional anisotropy emerged in schizophrenia only after age 35, and the rate of fractional anisotropy deterioration with age was constant and best modeled with a straight line. The slope of this line was 60% steeper in schizophrenia relative to comparison subjects, indicating a significantly faster rate of white matter deterioration with age. The rates of reduction of gray matter volume and fractional anisotropy were significantly faster in males than in females, but an interaction between sex and diagnosis was not evident.nnnCONCLUSIONSnThe findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.

Cortico-limbic network abnormalities in individuals with current and past major depressive disorder.

BACKGROUNDnBrain abnormalities in fronto-temporal structures have been implicated in major depressive disorder (MDD). This study aims to identify their anatomical distribution and their relation to the time course of the disease.nnnMETHODSnA whole-brain voxel based morphometry analysis was conducted to assess gray and white matter alterations in 56 participants with a lifetime history of MDD, including currently depressed (cMDD) and remitted patients (rMDD), and 33 matched healthy controls (HC).nnnRESULTSnCompared to HC, MDD participants showed increased white matter volume (WMV) in the uncinate fasciculus (UF) and decreased gray matter density (GMD) on the ventromedial prefrontal cortex (vmPFC). The increased WMV in UF was driven by both cMDD and rMDD groups and positively correlated with depression scores. The GMD decrease in the vmPFC resulted mainly from abnormalities in rMDD and was not correlated with depression scores. Finally, temporal UF and vmPFC white matter showed strong structural covariance suggesting functional interactions between these two brain regions.nnnLIMITATIONSnThe retrospective and cross-sectional design of the study limits the generalizability of the results. Information concerning ongoing treatment did not allow the exploration of interactions between medication and observed abnormalities. The duration of the remission period could have influenced abnormalities in the subgroup of remitted patients.nnnCONCLUSIONSnFronto-temporal alterations in MDD consist of alterations in a cortico-limbic network involving the ventromedial prefrontal cortex and temporal white matter tracts. State-like abnormalities in the UF survive remission and persist as trait-like abnormalities together with alteration in the vmPFC.

Reduced frontal white matter volume in children with early onset of adrenarche

While there is growing evidence that puberty affects brain development, very little is known about the structural brain changes associated with dehydroepiandrosterone (DHEA), an adrenal hormone that exhibits dramatic increases during adrenarche, the earliest phase of puberty. Moreover, no research has investigated whether relatively early exposure to DHEA (i.e., early adrenarche) during this period is associated with differences in brain structure. We ran a whole-brain voxel-based morphometry analysis on T1-weighted magnetic resonance imaging brain scans to compare gray (GMV) and white matter volumes (WMV) between children experiencing relatively early (n=41) vs. relatively late (n=44) adrenarche. We also investigated the correlations between GMV or WMV and DHEA levels, and finally, tested for sex differences in group and correlation analyses. We observed reduced frontal WMV in a cluster located on the left corona radiata in children experiencing earlier adrenarche. In addition, WMV in this area was negatively correlated with DHEA levels. We did not observe any effect of gender in both the group and the correlation analyses. Early onset of adrenarche (as defined by relatively early exposure to DHEA) may be associated with differences in the development of frontal white matter tracts.

Neuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume

Lithium and quetiapine are effective treatments for bipolar disorder, but their potential neuroprotective effects in humans remain unclear. A single blinded equivalence randomized controlled maintenance trial was conducted in a prospective cohort of first-episode mania (FEM) patients (n=26) to longitudinally compare the putative protective effects of lithium and quetapine on grey and white matter volume. A healthy control sample was also collected (n=20). Using structural MRI scans, voxel-wise grey and white matter volumes at baseline and changes over time in response to treatment were investigated. Patients were assessed at three time points (baseline, 3 and 12-month follow-up), whereas healthy controls were assessed at two time points (baseline and 12-month follow-up). Patients were randomized to lithium (serum level 0.6u2009mmolu2009l−1, n=20) or quetiapine (flexibly dosed up to 800u2009mg per day, n=19) monotherapy. At baseline, compared with healthy control subjects, patients with FEM showed reduced grey matter in the orbitofrontal cortex, anterior cingulate, inferior frontal gyrus and cerebellum. In addition, patients had reduced internal capsule white matter volume bilaterally (t1,66>3.20, P<0.01). Longitudinally, there was a significant treatment × time effect only in the white matter of the left internal capsule (F2,112=8.54, P<0.01). Post hoc testing showed that, compared with baseline, lithium was more effective than quetiapine in slowing the progression of white matter volume reduction after 12 months (t1,24=3.76, P<0.01). Our data support the role of lithium but not quetiapine therapy in limiting white matter reduction early in the illness course after FEM.

Baseline grey matter volume of non-transitioned "ultra high risk" for psychosis individuals with and without attenuated psychotic symptoms at long-term follow-up

INTRODUCTIONnTwo thirds of individuals identified as ultra-high risk (UHR) for psychosis do not transition to psychosis over the medium to long-term (non-transition; UHR-NT). Nevertheless, many of these individuals have persistent attenuated psychotic symptoms (APS). The current study examined whether there were differences in baseline grey matter volume (i.e. at initial identification as UHR) in UHR-NT individuals whom had APS compared to those without APS (No-APS) at medium to long-term follow-up.nnnMETHODSnParticipants were help-seeking individuals who were identified as being at UHR for psychosis between 2 and 12years previously (mean=7.5). The sample consisted of 109 participants who underwent a Magnetic Resonance Imaging scan at baseline and who had not been observed to develop a psychotic disorder over the follow-up period (UHR-NT). Using voxel-based morphometry, baseline grey matter volume (GMV) was compared between participants with (N=30) and without (N=79) APS at follow-up.nnnRESULTSnAt baseline, the APS and No-APS groups were clinically indistinguishable. At follow-up, the APS group had significantly worse symptoms and impaired functioning. Individuals with APS had reduced baseline GMV in frontal, temporal, posterior and cingulate regions compared to those without APS at follow-up. Reduced GMV was associated with more severe positive, negative and depressive symptoms and lower global functioning in the combined UHR-NT cohort. These associations were independent of later APS outcome.nnnDISCUSSIONnThis study found that differences in regional GMV are discernible at an early stage of UHR and may be specific to individuals who have APS and psychopathology at follow-up. Our findings suggest that lower GMV at baseline may confer neurobiological risk for later APS and/or increased psychopathology while the absence of these structural abnormalities might be protective.

The effect of a muscarinic receptor 1 gene variant on grey matter volume in schizophrenia

Previous research has demonstrated that individuals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test (WCST) than those who are heterozygous. This study sought to determine whether variation in the rs2067477 genotype was associated with differential changes in brain structure. Data from 227 patients with established schizophrenia or schizoaffective disorder were obtained from the Australian Schizophrenia Research Bank. Whole-brain voxel-based morphometry was performed to compare regional grey matter volume (GMV) between the 267C/C (N=191) and 267C/A (N=36) groups. Secondary analyses tested for an effect of genotype on cognition (the WCST was not available). Individuals who were homozygous (267C/C) demonstrated significantly reduced GMV in the right precentral gyrus compared to those who were heterozygous (267C/A). These preliminary results suggest that the rs2067477 genotype is associated with brain structure in the right precentral gyrus in individuals with schizophrenia/schizoaffective disorder. Future studies are required to replicate these results and directly link the volumetric reductions with specific cognitive processes.

Functional and Structural Alterations in the Cingulate Motor Area Relate to Decreased Fronto-Striatal Coupling in Major Depressive Disorder with Psychomotor Disturbances

Psychomotor disturbances are a classic feature of major depressive disorders. These can manifest as lack of facial expressions and decreased speech production, reduced body posture and mobility, and slowed voluntary movement. The neural correlates of psychomotor disturbances in depression are poorly understood but it has been suggested that outputs from the cingulate motor area (CMA) to striatal motor regions, including the putamen, could be involved. We used functional and structural magnetic resonance imaging to conduct a region-of-interest analysis to test the hypotheses that neural activation patterns related to motor production and gray matter volumes in the CMA would be different between depressed subjects displaying psychomotor disturbances (nu2009=u200913) and matched healthy controls (nu2009=u200913). In addition, we conducted a psychophysiological interaction analysis to assess the functional coupling related to self-paced finger-tapping between the caudal CMA and the posterior putamen in patients compared to controls. We found a cluster of increased neural activation, adjacent to a cluster of decreased gray matter volume in the caudal CMA in patients compared to controls. The functional coupling between the left caudal CMA and the left putamen during finger-tapping task performance was additionally decreased in patients compared to controls. In addition, the strength of the functional coupling between the left caudal CMA and the left putamen was negatively correlated with the severity of psychomotor disturbances in the patient group. In conclusion, we found converging evidence for involvement of the caudal CMA and putamen in the generation of psychomotor disturbances in depression.