Hippocampus abnormalities in at risk mental states for psychosis? A cross-sectional high resolution region of interest magnetic resonance imaging study

Background: Hippocampal volume (HV) reduction is well documented in schizophrenia. However, it is still unclear whether this change is a pre-existing vulnerability factor, a sign of disease progression, a consequence of environmental factors, such as drug use, antipsychotic medication, or malnutrition. The timing of HV changes is not well established, but a lack of macrostructural hippocampal brain abnormalities before disease onset would rather support a neuroprogressive illness model. Aim: To investigate the timing of HV changes in emerging psychosis. Methods: A cross-sectional MRI study of manually traced HVs in 37 individuals with an At Risk Mental State (ARMS) for psychosis, 23 individuals with First-Episode Psychosis (FEP), and 22 Healthy Controls (HC) was performed. We compared left and right HVs corrected for whole brain volume across groups using analysis of covariance (ANCOVA) with gender as a covariate. Sixteen of 37 ARMS individuals developed a psychotic disorder during follow up (ARMS-T). The mean duration of follow up in ARMS was 25.1 months. Results: The overall ANCOVA model comparing left HVs across FEP, ARMS and HC indicated a significant general group effect (p < .05) with largest volumes in ARMS and smallest in FEP. ARMS-T subjects had significantly larger left HVs compared to FE but no HV differences compared to HC (p < 0.05). Over all groups, we found an asymmetry between the left and right mean HVs and a strong effect of sex. Discussion: The present study suggests that macrostructural hippocampal abnormalities probably occur in the context of the first psychotic breakdown

Hippocampal volume in subjects at high risk of psychosis: a longitudinal MRI study

The hippocampal formation has been studied extensively in schizophrenic psychoses and alterations in hippocampal anatomy have been consistently reported. Chronic schizophrenia seems to be associated with bilateral hippocampal volume (HV) reduction, while in patients with an at-risk mental state (ARMS) there are contradictory results. This is the first region of interest (ROI) based follow-up MRI study of hippocampal volume comparing ARMS individuals with and without transition to psychosis. The aim was to investigate the timing of HV changes in ARMS in the early phase of psychosis. METHODS: Magnetic resonance imaging data from 18 antipsychotic-naive individuals with an ARMS were collected within the FePsy-clinic for early detection of psychoses. During follow-up 8 subjects transitioned to psychosis (ARMS-T) and 10 did not (ARMS-NT). Subjects were re-scanned after the onset of psychosis or at the end of the follow-up if they did not develop psychosis. RESULTS: Across both groups there was a significant decrease in HV over time (p&lt;0.05). There was no significant difference in progression between ARMS-T and ARMS-NT. Antipsychotic medication at follow up was associated with increased HV (p&lt;0.05). CONCLUSIONS: We found a decrease of HV over time in subjects with an ARMS, independently of clinical outcome. We may speculate that the decrease of HV over time might reflect brain degeneration processes

Abnormal Functional Integration of Thalamic Low Frequency Oscillation in the BOLD Signal After Acute Heroin Treatment

Heroin addiction is a severe relapsing brain disorder associated with impaired cognitive control, including deficits in attention allocation. The thalamus has a high density of opiate receptors and is critically involved in orchestrating cortical activity during cognitive control. However, there have been no studies on how acute heroin treatment modulates thalamic activity. In a cross-over, double-blind, vehicle-controlled study, 29 heroin-maintained outpatients were studied after heroin and placebo administration, while 20 healthy controls were included for the placebo condition only. Resting-state functional magnetic resonance imaging was used to analyze functional integration of the thalamus by three different resting state analysis techniques. Thalamocortical functional connectivity (FC) was analyzed by seed-based correlation, while intrinsic thalamic oscillation was assessed by analysis of regional homogeneity (ReHo) and the fractional amplitude of low frequency fluctuations (fALFF). Relative to the placebo treatment and healthy controls, acute heroin administration reduced thalamocortical FC to cortical regions, including the frontal cortex, while the reductions in FC to the mediofrontal cortex, orbitofrontal cortex, and frontal pole were positively correlated with the plasma level of morphine, the main psychoactive metabolite of heroin. Furthermore, heroin treatment was associated with increased thalamic ReHo and fALFF values, whereas fALFF following heroin exposure correlated negatively with scores of attentional control. The heroin-associated increase in fALFF was mainly dominated by slow-4 (0.027-0.073 Hz) oscillations. Our findings show that there are acute effects of heroin within the thalamocortical system and may shed new light on the role of the thalamus in cognitive control in heroin addiction. Future research is needed to determine the underlying physiological mechanisms and their role in heroin addiction

Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis.

OBJECTIVE: To assess the impact of fingolimod (FTY720) therapy on magnetic resonance imaging measures of inflammatory activity and tissue damage in patients participating in a 2-year, placebo-controlled, phase 3 study. DESIGN: Patients with active relapsing-remitting multiple sclerosis were randomized to receive fingolimod, 0.5 mg; fingolimod, 1.25 mg; or placebo for 2 years. Standardized magnetic resonance imaging scans were obtained at months 0, 6, 12, and 24 and centrally evaluated for number and volume of T1 gadolinium-enhancing, T2 hyperintense, and T1 hypointense lesions and for percentage of brain volume change. Findings were compared across subgroups by treatment and baseline characteristics. SETTING: Worldwide, multicenter clinical trial. PATIENTS: Patients were part of the fingolimod FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) clinical trial for relapsing-remitting multiple sclerosis (N=1272). MAIN OUTCOME MEASURES: We measured the effect of therapy on acute inflammatory activity, burden of disease, and irreversible loss of brain volume. RESULTS: Fingolimod therapy resulted in rapid and sustained reductions in inflammatory lesion activity as assessed by gadolinium-enhancing and new/newly enlarged T2 lesions after 6, 12, and 24 months of therapy (P.001, all comparisons vs placebo). Changes in T2 hyperintense and T1 hypointense lesion volume also significantly favored fingolimod (P.05, all comparisons). Fingolimod, 0.5 mg (licensed dose), significantly reduced brain volume loss during months 0 to 6, 0 to 12, 12 to 24, and 0 to 24 (P.05, all comparisons) vs placebo, and subgroup analyses confirmed these effects over 2 years irrespective of the presence/absence of gadolinium-enhancing lesions, T2 lesion load, previous treatment status, or level of disability. CONCLUSION: These results, coupled with the significant reductions in relapse rates and disability progression reported previously, support the positive impact on long-term disease evolution. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00289978clinical trial, phase iiijournal articlemulticenter studyrandomized controlled trialresearch support, non-u.s. gov't2012 Octimporte

Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix® HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotyp

Effects of Cannabis on Impulsivity: A Systematic Review of Neuroimaging Findings

We conducted a systematic review to assess the evidence for specific effects of cannabis on impulsivity, disinhibition and motor control. The review had a specific focus on neuroimaging findings associated with acute and chronic use of the drug and covers literature published up until May 2012. Seventeen studies were identified, of which 13 met the inclusion criteria; three studies investigated acute effects of cannabis (1 fMRI, 2 PET), while six studies investigated non-acute functional effects (4 fMRI, 2 PET), and four studies investigated structural alterations. Functional imaging studies of impulsivity studies suggest that prefrontal blood flow is lower in chronic cannabis users than in controls. Studies of acute administration of THC or marijuana report increased brain metabolism in several brain regions during impulsivity tasks. Structural imaging studies of cannabis users found differences in reduced prefrontal volumes and white matter integrity that might mediate the abnormal impulsivity and mood observed in marijuana users. To address the question whether impulsivity as a trait precedes cannabis consumption or whether cannabis aggravates impulsivity and discontinuation of usage more longitudinal study designs are warranted

Reduced volume of the nucleus accumbens in heroin addiction

The neural mechanisms of heroin addiction are still incompletely understood, even though modern neuroimaging techniques offer insights into disease-related changes in vivo. While changes on cortical structure have been reported in heroin addiction, evidence from subcortical areas remains underrepresented. Functional imaging studies revealed that the brain reward system and particularly the nucleus accumbens (NAcc) play a pivotal role in the pathophysiology of drug addiction. The aim of this study was to investigate whether there was a volume difference of the NAcc in heroin addiction in comparison to healthy controls. A further aim was to correlate subcortical volumes with clinical measurements on negative affects in addiction. Thirty heroin-dependent patients under maintenance treatment with diacetylmorphine and twenty healthy controls underwent structural MRI scanning at 3T. Subcortical segmentation analysis was performed using FMRIB's Integrated Registration and Segmentation Tool function of FSL. The State-Trait Anxiety Inventory and the Beck Depression Inventory were used to assess trait anxiety and depressive symptoms, respectively. A decreased volume of the left NAcc was observed in heroin-dependent patients compared to healthy controls. Depression score was negatively correlated with left NAcc volume in patients, whereas a positive correlation was found between the daily opioid dose and the volume of the right amygdala. This study indicates that there might be structural differences of the NAcc in heroin-dependent patients in comparison with healthy controls. Furthermore, correlations of subcortical structures with negative emotions and opioid doses might be of future relevance for the investigation of heroin addiction

Increased functional connectivity in the resting-state basal ganglia network after acute heroin substitution

Reinforcement signals in the striatum are known to be crucial for mediating the subjective rewarding effects of acute drug intake. It is proposed that these effects may be more involved in early phases of drug addiction, whereas negative reinforcement effects may occur more in later stages of the illness. This study used resting-state functional magnetic resonance imaging to explore whether acute heroin substitution also induced positive reinforcement effects in striatal brain regions of protracted heroin-maintained patients. Using independent component analysis and a dual regression approach, we compared resting-state functional connectivity (rsFC) strengths within the basal ganglia/limbic network across a group of heroin-dependent patients receiving both an acute infusion of heroin and placebo and 20 healthy subjects who received placebo only. Subsequent correlation analyses were performed to test whether the rsFC strength under heroin exposure correlated with the subjective rewarding effect and with plasma concentrations of heroin and its main metabolites morphine. Relative to the placebo treatment in patients, heroin significantly increased rsFC of the left putamen within the basal ganglia/limbic network, the extent of which correlated positively with patients' feelings of rush and with the plasma level of morphine. Furthermore, healthy controls revealed increased rsFC of the posterior cingulate cortex/precuneus in this network relative to the placebo treatment in patients. Our results indicate that acute heroin substitution induces a subjective rewarding effect via increased striatal connectivity in heroin-dependent patients, suggesting that positive reinforcement effects in the striatum still occur after protracted maintenance therapy

Multivariate pattern classification of gray matter pathology in multiple sclerosis

Univariate analyses have identified gray matter (GM) alterations in different groups of MS patients. While these methods detect differences on the basis of the single voxel or cluster, multivariate methods like support vector machines (SVM) identify the complex neuroanatomical patterns of GM differences. Using multivariate linear SVM analysis and leave-one-out cross-validation, we aimed at identifying neuroanatomical GM patterns relevant for individual classification of MS patients. We used SVM to separate GM segmentations of T1-weighted three-dimensional magnetic resonance (MR) imaging scans within different age- and sex-matched groups of MS patients with either early (n = 17) or late MS (n = 17) (contrast I), low (n = 20) or high (n = 20) white matter lesion load (contrast II), and benign MS (BMS, n = 13) or non-benign MS (NBMS, n = 13) (contrast III) scanned on a single 1.5 T MR scanner. GM patterns most relevant for individual separation of MS patients comprised cortical areas of all the cerebral lobes as well as deep GM structures, including the thalamus and caudate. The patterns detected were sufficiently informative to separate individuals of the respective groups with high sensitivity and specificity in 85% (contrast I), 83% (contrast II) and 77% (contrast III) of cases. The study demonstrates that neuroanatomical spatial patterns of GM segmentations contain information sufficient for correct classification of MS patients at the single case level, thus making multivariate SVM analysis a promising clinical application