Juan Bustillo

A Baseline for the Multivariate Comparison of Resting-State Networks

As the size of functional and structural MRI datasets expands, it becomes increasingly important to establish a baseline from which diagnostic relevance may be determined, a processing strategy that efficiently prepares data for analysis, and a statistical approach that identifies important effects in a manner that is both robust and reproducible. In this paper, we introduce a multivariate analytic approach that optimizes sensitivity and reduces unnecessary testing. We demonstrate the utility of this mega-analytic approach by identifying the effects of age and gender on the resting-state networks (RSNs) of 603 healthy adolescents and adults (mean age: 23.4 years, range: 12–71 years). Data were collected on the same scanner, preprocessed using an automated analysis pipeline based in SPM, and studied using group independent component analysis. RSNs were identified and evaluated in terms of three primary outcome measures: time course spectral power, spatial map intensity, and functional network connectivity. Results revealed robust effects of age on all three outcome measures, largely indicating decreases in network coherence and connectivity with increasing age. Gender effects were of smaller magnitude but suggested stronger intra-network connectivity in females and more inter-network connectivity in males, particularly with regard to sensorimotor networks. These findings, along with the analysis approach and statistical framework described here, provide a useful baseline for future investigations of brain networks in health and disease.

Selective Cognitive Impairments Associated with NMDA Receptor Blockade in Humans

Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) may be involved in the pathophysiology of schizophrenia. NMDAR antagonists like ketamine induce schizophrenia-like features in humans. In rodent studies, NMDAR antagonism impairs learning by disrupting long-term potentiation (LTP) in the hippocampus. This study investigated the effects of ketamine on spatial learning (acquisition) vs retrieval in a virtual Morris water task in humans. Verbal fluency, working memory, and learning and memory of verbal information were also assessed. Healthy human subjects participated in this double-blinded, placebo-controlled study. On two separate occasions, ketamine/placebo was administered and cognitive tasks were assessed in association with behavioral ratings. Ketamine impaired learning of spatial and verbal information but retrieval of information learned prior to drug administration was preserved. Schizophrenia-like symptoms were significantly related to spatial and verbal learning performance. Ketamine did not significantly impair attention, verbal fluency, or verbal working memory task performance. Spatial working memory was slightly impaired. In conclusion, these results provide evidence for ketamines differential impairment of verbal and spatial learning vs retrieval. By using the Morris water task, which is hippocampal-dependent, this study helps bridge the gap between nonhuman animal and human NMDAR antagonism research. Impaired cognition is a core feature of schizophrenia. A better understanding of NMDA antagonism, its physiological and cognitive consequences, may provide improved models of psychosis and cognitive therapeutics.

1H-MRS at 4 Tesla in minimally treated early schizophrenia

We investigated glutamate-related neuronal dysfunction in the anterior cingulate (AC) early in schizophrenia before and after antipsychotic treatment. A total of 14 minimally treated schizophrenia patients and 10 healthy subjects were studied with single-voxel proton magnetic resonance spectroscopy (1H-MRS) of the AC, frontal white matter and thalamus at 4 T. Concentrations of N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln) and Gln/Glu ratios were determined and corrected for the partial tissue volume. Patients were treated with antipsychotic medication following a specific algorithm and 1H-MRS was repeated after 1, 6 and 12 months. There were group × region interactions for baseline NAA (P=0.074) and Gln/Glu (P=0.028): schizophrenia subjects had lower NAA (P=0.045) and higher Gln/Glu (P=0.006) in the AC before treatment. In addition, AC Gln/Glu was inversely related to AC NAA in the schizophrenia (P=0.0009) but not in the control group (P=0.92). Following antipsychotic treatment, there were no further changes in NAA, Gln/Glu or any of the other metabolites in any of the regions studied. We conclude that early in the illness, schizophrenia patients already show abnormalities in glutamatergic metabolism and reductions in NAA consistent with glutamate-related excitotoxicity.

Global White Matter Abnormalities in Schizophrenia: A Multisite Diffusion Tensor Imaging Study

BACKGROUND Emerging evidence implicates white matter (WM) abnormalities in the pathophysiology of schizophrenia. However, there is considerable heterogeneity in the presentation of WM abnormalities in the existing studies. The object of this study was to evaluate WM integrity in a large sample of patients with first-episode (FE) and chronic schizophrenia in comparison to matched control groups. Our goal was to assess whether WM findings occurred early in the illness or whether these abnormalities developed with the illness over time. METHODS Participants included 114 patients with schizophrenia (31 FE and 83 chronic patients) and 138 matched controls. High-resolution structural and diffusion tensor images were obtained on all participants. Measures of fractional anisotropy (FA) were calculated for the 4 cortical lobes and the cerebellum and brain stem. RESULTS FA was significant lower in patients vs controls in the whole brain and individually in the frontal, parietal, occipital, and temporal lobes. FA was not significantly different in the brain stem or cerebellum. FA differences were significant only in patients with chronic schizophrenia and not in the FE group. CONCLUSIONS We found global differences in the WM microstructure in patients with chronic but not FE schizophrenia. These findings suggest progressive alterations in WM microstructure.

Logic and justification for dimensional assessment of symptoms and related clinical phenomena in psychosis: Relevance to DSM-5

Work on the causes and treatment of schizophrenia and other psychotic disorders has long recognized the heterogeneity of the symptoms that can be displayed by individuals with these illnesses. Further, researchers have increasingly emphasized the ways in which the severity of different symptoms of this illness can vary across individuals, and have provided evidence that the severity of such symptoms can predict other important aspects of the illness, such as the degree of cognitive and/or neurobiological deficits. Additionally, research has increasingly emphasized that the boundaries between nosological entities may not be categorical and that the comorbidity of disorders may reflect impairments in common dimensions of genetic variation, human behavior and neurobiological function. As such, it is critical to focus on a dimensional approach to the assessment of symptoms and clinically relevant phenomena in psychosis, so as to increase attention to and understanding of the causes and consequences of such variation. In the current article, we review the logic and justification for including dimensional assessment of clinical symptoms in the evaluation of psychosis in the Fifth Edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5).

Proton Echo-Planar Spectroscopic Imaging of J-Coupled Resonances in Human Brain at 3 and 4 Tesla

In this multicenter study, 2D spatial mapping of J‐coupled resonances at 3T and 4T was performed using short‐TE (15 ms) proton echo‐planar spectroscopic imaging (PEPSI). Water‐suppressed (WS) data were acquired in 8.5 min with 1‐cm3 spatial resolution from a supraventricular axial slice. Optimized outer volume suppression (OVS) enabled mapping in close proximity to peripheral scalp regions. Constrained spectral fitting in reference to a non‐WS (NWS) scan was performed with LCModel using correction for relaxation attenuation and partial‐volume effects. The concentrations of total choline (tCho), creatine + phosphocreatine (Cr+PCr), glutamate (Glu), glutamate + glutamine (Glu+Gln), myo‐inositol (Ins), NAA, NAA+NAAG, and two macromolecular resonances at 0.9 and 2.0 ppm were mapped with mean Cramer‐Rao lower bounds (CRLBs) between 6% and 18% and ∼150‐cm3 sensitive volumes. Aspartate, GABA, glutamine (Gln), glutathione (GSH), phosphoethanolamine (PE), and macromolecules (MMs) at 1.2 ppm were also mapped, although with larger mean CRLBs between 30% and 44%. The CRLBs at 4T were 19% lower on average as compared to 3T, consistent with a higher signal‐to‐noise ratio (SNR) and increased spectral resolution. Metabolite concentrations were in the ranges reported in previous studies. Glu concentration was significantly higher in gray matter (GM) compared to white matter (WM), as anticipated. The short acquisition time makes this methodology suitable for clinical studies. Magn Reson Med, 2007.

Structure of the psychotic disorders classification in DSM‐5

Schizophrenia spectrum disorders attract great interest among clinicians, researchers, and the lay public. While the diagnostic features of schizophrenia have remained unchanged for more than 100 years, the mechanism of illness has remained elusive. There is increasing evidence that the categorical diagnosis of schizophrenia and other psychotic disorders contributes to this lack of progress. The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) continues the categorical classification of psychiatric disorders since the research needed to establish a new nosology of equal or greater validity is lacking. However, even within a categorical system, the DSM-5 aims to capture the underlying dimensional structure of psychosis. The domains of psychopathology that define psychotic disorders are presented not simply as features of schizophrenia. The level, the number, and the duration of psychotic signs and symptoms are used to demarcate psychotic disorders from each other. Finally, the categorical assessment is complemented with a dimensional assessment of psychosis that allows for more specific and individualized assessment of patients. The structure of psychosis as outlined in the DSM-5 may serve as a stepping-stone towards a more valid classification system, as we await new data to redefine psychotic disorders.

Patterns of Gray Matter Abnormalities in Schizophrenia Based on an International Mega-analysis

Analyses of gray matter concentration (GMC) deficits in patients with schizophrenia (Sz) have identified robust changes throughout the cortex. We assessed the relationships between diagnosis, overall symptom severity, and patterns of gray matter in the largest aggregated structural imaging dataset to date. We performed both source-based morphometry (SBM) and voxel-based morphometry (VBM) analyses on GMC images from 784 Sz and 936 controls (Ct) across 23 scanning sites in Europe and the United States. After correcting for age, gender, site, and diagnosis by site interactions, SBM analyses showed 9 patterns of diagnostic differences. They comprised separate cortical, subcortical, and cerebellar regions. Seven patterns showed greater GMC in Ct than Sz, while 2 (brainstem and cerebellum) showed greater GMC for Sz. The greatest GMC deficit was in a single pattern comprising regions in the superior temporal gyrus, inferior frontal gyrus, and medial frontal cortex, which replicated over analyses of data subsets. VBM analyses identified overall cortical GMC loss and one small cluster of increased GMC in Sz, which overlapped with the SBM brainstem component. We found no significant association between the component loadings and symptom severity in either analysis. This mega-analysis confirms that the commonly found GMC loss in Sz in the anterior temporal lobe, insula, and medial frontal lobe form a single, consistent spatial pattern even in such a diverse dataset. The separation of GMC loss into robust, repeatable spatial patterns across multiple datasets paves the way for the application of these methods to identify subtle genetic and clinical cohort effects.

What have we learned from proton magnetic resonance spectroscopy about schizophrenia? A critical update.

Purpose of review This review discusses recent studies investigating schizophrenia with proton magnetic resonance spectroscopy including the first meta-analysis [Steen RG, Hamer RM, Lieberman JA. Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis. Neuropsychology 2005; 30:1949–1962]. We also highlight methodological issues and suggest a modality for future research to further explore glutamatergic dysfunction in schizophrenia. Recent findings Despite methodological differences, spectroscopy studies with schizophrenia show reductions in N-acetylaspartate in the medial temporal and prefrontal regions. Other areas such as the anterior cingulate, parietal cortex thalamus, and cerebellum may also have N-acetylaspartate reductions. The proton magnetic resonance spectroscopy studies at higher fields and with shorter echo time have revealed abnormalities in glutamate and glutamine. Animal studies have shown that the discrepancies in metabolites between patients and controls are not due to antipsychotic medication exposure, and that chronic exposure to N-methyl-D-aspartate antagonists has produced decreased N-acetylaspartate in the temporal cortex. The human and animal studies both support an excitoxic glutamatergically mediated process that may explain decreased N-acetylaspartate, volume loss, and the poor outcomes of schizophrenia. Summary Use of higher field strengths and longitudinal studies may reveal a progressive excitoxic glutamatergic process that leads to N-acetylaspartate and volume reductions. This may lead to the development of neuroprotective agents that change the course of schizophrenia.

Altered Expression of Genes Involved in GABAergic Transmission and Neuromodulation of Granule Cell Activity in the Cerebellum of Schizophrenia Patients

OBJECTIVE Deficits in gamma-aminobutyric acid (GABA) signaling have been described in the prefrontal cortex, limbic system, and cerebellum in individuals with schizophrenia. The purpose of the present study was to further investigate cerebellar gene expression alterations as they relate to decreases in GABAergic transmission by examining the expression of GABAergic markers, N-methyl-d-aspartic-acid (NMDA) receptor subunits, and cerebellum neuromodulators in individuals with schizophrenia. METHOD Subjects were postmortem men with a diagnosis of schizophrenia (N=13) and a postmortem interval-matched non-psychiatric male comparison group (N=13). The authors utilized real-time-quantitative polymerase chain reaction (PCR) to measure mRNA levels of the following GABAergic markers: glutamic acid decarboxylase (GAD) 65 and 67; GABA plasma membrane transporter-1 (GAT-1); GABA type A (GABA(A)) receptor subunits alpha(6), beta(3), and delta; and parvalbumin. In addition, real-time-quantitative PCR was utilized to assess mRNA levels of the NMDA receptor (NR) subunits NR1, NR2-A, NR2-B, NR2-C, and NR2-D as well as the cerebellar neuromodulators glutamate receptor (GluR)-6, kainate-preferring glutamate receptor subunit-2 (KA2), metabotropic glutamate receptor (mGluR)-2 and mGluR3, and neuronal nitric oxide synthase. Measurements for mRNA levels were determined using lateral cerebellar hemisphere tissue from both schizophrenia and comparison subjects. RESULTS Schizophrenia subjects showed significant decreases in mRNA levels of GAD(67), GAD(65), GAT-1, mGluR2, and neuronal nitric oxide synthase. Increases in GABA(A)-alpha(6 )and GABA(A)-delta as well as GluR6 and KA2 were also observed. Medication effects on the expression of the same genes were examined in rats treated with either haloperidol (Sprague-Dawley rats [N=16]) or clozapine (Long-Evans rats [N=20]). Both haloperidol and clozapine increased the levels of GAD(67) in the cerebellum and altered the expression of other cerebellar mRNAs. CONCLUSIONS These findings suggest that GABA transmission is decreased in the cerebellar cortices in individuals with schizophrenia and additional gene expression changes may reflect an attempt to increase GABA neurotransmission at the cerebellar glomerulus.