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It is becoming increasingly clear that longer duration of untreated psychosis (DUP) is associated with adverse clinical outcomes in patients with psychosis spectrum disorders. Because this association is often cited when justifying early intervention efforts, it is imperative to better understand underlying biological mechanisms. We enrolled 66 antipsychotic-naïve first-episode psychosis (FEP) patients and 45 matched healthy controls in this trial. At baseline, we used a human connectome style diffusion-weighted imaging (DWI) sequence to quantify white matter integrity in both groups. Patients then received 16 weeks of treatment with risperidone, 51 FEP completed the trial. We compared whole-brain fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD), and radial diffusivity between groups. To test if structural white matter integrity mediates the relationship between longer DUP and poorer treatment response, we fit a mediator model and estimated indirect effects. We found decreased whole-brain FA and AD in medication-naive FEP compared with controls. In patients, lower FA was correlated with longer DUP (r = -0.32; p = 0.03) and poorer subsequent response to antipsychotic treatment (r = 0.40; p = 0.01). Importantly, we found a significant mediation effect for FA (indirect effect: -2.70; p = 0.03), indicating that DUP exerts its effects on treatment response through affecting white matter integrity. Our data provide empirical support to the idea the DUP may have fundamental pathogenic effects on the natural history of psychosis, suggest a biological mechanism underlying this phenomenon, and underscore the importance of early intervention efforts in this disabling neuropsychiatric syndrome.
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Antipsicóticos , Transtornos Psicóticos , Substância Branca , Antipsicóticos/uso terapêutico , Encéfalo/diagnóstico por imagem , Humanos , Transtornos Psicóticos/tratamento farmacológico , Risperidona/uso terapêutico , Substância Branca/diagnóstico por imagemRESUMO
There is no pharmacological treatment to remediate cognitive impairment in schizophrenia (SZ). It is imperative to characterize underlying pathologies of memory processing in order to effectively develop new treatments. In this longitudinal study, we combined functional magnetic resonance imaging during a memory encoding task with proton MR spectroscopy to measure hippocampal glutamate + glutamine (Glx). Seventeen SZ were scanned while unmedicated and after 6 weeks of treatment with risperidone and compared to a group of matched healthy controls (HC) scanned 6 weeks apart. Unmedicated patients showed reduced blood oxygen level dependent (BOLD) response in several regions, including the hippocampus, and greater BOLD response in regions of the default mode network (DMN) during correct memory encoding. Post hoc contrasts from significant group by time interactions indicated reduced hippocampal BOLD response at baseline with subsequent increase following treatment. Hippocampal Glx was not different between groups at baseline, but at week 6, hippocampal Glx was significantly lower in SZ compared to HC. Finally, in unmedicated SZ, higher hippocampal Glx predicted less deactivation of the BOLD response in regions of the DMN. Using 2 brain imaging modalities allowed us to concurrently investigate different mechanisms involved in memory encoding dysfunction in SZ. Hippocampal pathology during memory encoding stems from decreased hippocampal recruitment and faulty deactivation of the DMN, and hippocampal recruitment during encoding can be modulated by antipsychotic treatment. High Glx in unmedicated patients predicted less deactivation of the DMN; these results suggest a mechanism by which faulty DMN deactivation, a hallmark of pathological findings in SZ, is achieved.
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Antipsicóticos/farmacologia , Disfunção Cognitiva , Rede de Modo Padrão , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Hipocampo , Memória/fisiologia , Esquizofrenia , Adulto , Antipsicóticos/administração & dosagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Rede de Modo Padrão/diagnóstico por imagem , Rede de Modo Padrão/efeitos dos fármacos , Rede de Modo Padrão/metabolismo , Rede de Modo Padrão/fisiopatologia , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Memória Episódica , Rememoração Mental/fisiologia , Espectroscopia de Prótons por Ressonância Magnética , Reconhecimento Psicológico/fisiologia , Risperidona/farmacologia , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Resultado do Tratamento , Adulto JovemRESUMO
Abnormalities in resting state connectivity in schizophrenia (SZ) are now well established, but the biological substrates of these functional alterations remain to be elucidated. We performed a combined functional magnetic resonance imaging and magnetic resonance spectroscopy study in 22 unmedicated patients with SZ and 22 matched healthy controls (HCs) to evaluate resting state functional connectivity of the hippocampus and Glx/Cr (a combined glutamate + glutamine peak normalized to creatine) in the hippocampus and investigate functional and neurometabolic abnormalities and examine the relationship between these. Functional connectivity between the left hippocampus and bilateral precuneus was significantly decreased in unmedicated patients with SZ when compared to HCs [t(4.22), cluster extent (kE) = 751, PFDRcorr = 0.001, Montreal Neurological Institute coordinates: x = -4, y = -56, z = 44]. Glx/Cr in the hippocampus was significantly elevated in SZ (HC: mean = 0.60+/-0.10 SZ: 0.67+/-0.10; F = 5.742; P = 0.02), but was not correlated with functional connectivity deficits (P > 0.05). In this study, we found hippocampal resting state functional connectivity deficits to the precuneus in unmedicated patients with SZ and an increase of Glx/Cr in the hippocampus, but did not observe a direct relationship between these abnormalities. However, our findings do not exclude the possibility of a shared underlying pathology, which warrants further investigation.
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Ácido Glutâmico/metabolismo , Hipocampo/fisiopatologia , Lobo Parietal/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Mapeamento Encefálico , Creatina/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/fisiopatologia , Espectroscopia de Prótons por Ressonância Magnética , DescansoRESUMO
BACKGROUND: Heterogeneity in the etiology, pathophysiology, and clinical features of schizophrenia challenges clinicians and researchers. A helpful approach could be stratifying patients according to the presence or absence of clinical features of the deficit syndrome (DS). DS is characterized by enduring and primary negative symptoms, a clinically less heterogeneous subtype of the illness, and patients with features of DS are thought to present abnormal brain network characteristics, however, this idea has received limited attention. We investigated functional brain network topology in patients displaying deficit features and those who do not. DESIGN: We applied graph theory analytics to resting-state functional magnetic resonance imaging data of 61 antipsychotic medication-naïve first episode psychosis patients, 18 DS and 43 non-deficit schizophrenia (NDS), and 72 healthy controls (HC). We quantified small-worldness, global and nodal efficiency measures, shortest path length, nodal local efficiency, and synchronization and contrasted them among the 3 groups. RESULTS: DS presented decreased network integration and segregation compared to HC and NDS. DS showed lower global efficiency, longer global path lengths, and lower global local efficiency. Nodal efficiency was lower and the shortest path length was longer in DS in default mode, ventral attention, dorsal attention, frontoparietal, limbic, somatomotor, and visual networks compared to HC. Compared to NDS, DS showed lower efficiency and longer shortest path length in default mode, limbic, somatomotor, and visual networks. CONCLUSIONS: Our data supports increasing evidence, based on topological perturbations of the functional connectome, that deficit syndrome may be a distinct form of the illness.
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Conectoma , Imageamento por Ressonância Magnética , Rede Nervosa , Transtornos Psicóticos , Esquizofrenia , Humanos , Transtornos Psicóticos/fisiopatologia , Transtornos Psicóticos/diagnóstico por imagem , Masculino , Feminino , Adulto , Adulto Jovem , Esquizofrenia/fisiopatologia , Esquizofrenia/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Rede Nervosa/diagnóstico por imagem , AdolescenteRESUMO
Epidemiologic, genetic, and neurobiological studies suggest considerable overlap between schizophrenia and mood disorders. Importantly, both disorders are associated with a broad range of cognitive deficits as well as altered glutamatergic and GABAergic neurometabolism. We conducted a systematic review of magnetic resonance spectroscopy (MRS) studies investigating the relationship between glutamatergic and GABAergic neurometabolites and cognition in schizophrenia spectrum disorders and mood disorders. A literature search in Pubmed of studies published before April 15, 2019 was conducted and 37 studies were deemed eligible for systematic review. We found that alterations in glutamatergic and GABAergic neurotransmission have been identified relatively consistently in both schizophrenia and mood disorders. However, because of the vast heterogeneity of published studies in terms of illness stage, medication exposure, MRS acquisition parameters and data post-processing strategies, we still do not understand the relationship between those neurotransmitters and cognitive dysfunction in mental illness, which is a critical initial step for rational drug development. Our findings emphasize the need for coordinated multi-center studies that characterize cognitive function and its biological substrates in large and well-defined clinical populations, using harmonized imaging sequences and analytical methods with the goal to elucidate the underlying pathophysiological mechanisms and to inform future clinical trials.
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Disfunção Cognitiva , Esquizofrenia , Humanos , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Ácido Glutâmico , Transtornos do Humor/diagnóstico por imagem , Transtornos do Humor/etiologia , Encéfalo/diagnóstico por imagem , Espectroscopia de Ressonância Magnética , Disfunção Cognitiva/diagnóstico por imagem , Ácido gama-AminobutíricoRESUMO
Importance: To make progress toward precision psychiatry, it is crucial to move beyond case-control studies and instead capture individual variations and interpret them in the context of a normal range of biological systems. Objective: To evaluate whether baseline deviations from a normative reference range in subcortical volumes are better predictors of antipsychotic treatment response than raw volumes in patients with first-episode psychosis (FEP) who were naive to antipsychotic medication. Design, Setting, and Participants: In this prospective longitudinal study, patients with first-episode psychosis who were referred from different clinical settings (emergency department, inpatient units, and outpatient clinics) at the University of Alabama at Birmingham were included. A total of 286 patients were screened, 114 consented, 104 enrolled in the treatment trial, and 85 completed the trial. Patients were observed for 16 weeks. Controls were matched by age and sex. Data were collected between June 2016 and July 2021, and data were analyzed from August 2021 to June 2022. Interventions: Risperidone on a flexible dosing scheme for 16 weeks. There was an option to switch to aripiprazole for excessive adverse effects. Main Outcomes and Measures: The main outcome of this study was to evaluate, in patients with FEP who were naive to antipsychotic medication, the association of baseline raw volumes and volume deviations in subcortical brain regions with response to antipsychotic medication. Raw brain volumes or volume deviation changes after treatment were not examined. Results: Of 190 included participants, 111 (58.4%) were male, and the mean (SD) age was 23.7 (5.5) years. Volumes and deviations were quantified in 98 patients with FEP, and data from 92 controls were used as comparison for case-control contrasts and reference curve calibration. In case-control contrasts, patients with FEP had lower raw thalamus (P = .002; F = 9.63; df = 1), hippocampus (P = .009; F = 17.23; df = 1), amygdala (P = .01; F = 6.55; df = 1), ventral diencephalon (P = .03; F = 4.84; df = 1), and brainstem volumes (P = .004; F = 8.39; df = 1). Of 98 patients, 36 patients with FEP (36%) displayed extreme deviations. Associations with treatment response significantly differed between raw volume and deviation measures in the caudate (z = -2.17; P = .03) and putamen (z = -2.15; P = .03). Conclusions and Relevance: These data suggest that normative modeling allows capture of interindividual heterogeneity of regional brain volumes in patients with FEP and characterize structural pathology in a clinically relevant fashion. This holds promise for progress in precision medicine in psychiatry, where group-level studies have failed to derive reliable maps of structural pathology.
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Antipsicóticos , Transtornos Psicóticos , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos de Casos e Controles , Estudos Longitudinais , Imageamento por Ressonância Magnética , Estudos Prospectivos , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologiaRESUMO
A goal of this study was to evaluate the function of the anterior cingulate cortex (ACC) and of the dorsolateral prefrontal cortex (DLPFC) in medicated patients with schizophrenia (SZ), a small group of first-degree relatives, and healthy controls using a visual delayed match-to-sample task in conjunction with functional magnetic resonance imaging (fMRI). To mitigate performance differences between SZ and healthy controls, we used a novel task that allows for individualized adjustment of task difficulty to match ability level. We also trained participants on the task prior to scanning. Using an event-related design, we modeled three components of the match-to-sample trial: visual encoding, delay, and discrimination. We did not find significant differences in ACC/medial frontal cortex activation between the groups. However, compared to healthy controls, SZ showed decreased activation in visual processing areas during the encoding and discrimination phases of the task and in the ventrolateral prefrontal cortex during the delay. These findings emphasize the tendency of schizophrenia subjects to solve perceptual memory problems by engaging diverse regions.
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Mapeamento Encefálico , Córtex Pré-Frontal/patologia , Esquizofrenia/complicações , Esquizofrenia/patologia , Percepção Espacial/fisiologia , Transtornos da Visão/etiologia , Adulto , Análise de Variância , Tomada de Decisões , Família/psicologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Oxigênio/sangue , Estimulação Luminosa , Córtex Pré-Frontal/irrigação sanguínea , Escalas de Graduação Psiquiátrica , Tempo de Reação/fisiologia , Adulto JovemRESUMO
Schizophrenia is a complex neuropsychiatric disorder with a diverse clinical phenotype that has a substantial personal and public health burden. To advance the mechanistic understanding of the illness, neuroimaging can be utilized to capture different aspects of brain pathology in vivo, including brain structural integrity deficits, functional dysconnectivity, and altered neurotransmitter systems. In this review, we consider a number of key scientific questions relevant in the context of neuroimaging studies aimed at unraveling the pathophysiology of schizophrenia and take the opportunity to reflect on our progress toward advancing the mechanistic understanding of the illness. Our data is congruent with the idea that the brain is fundamentally affected in the illness, where widespread structural gray and white matter involvement, functionally abnormal cortical and subcortical information processing, and neurometabolic dysregulation are present in patients. Importantly, certain brain circuits appear preferentially affected and subtle abnormalities are already evident in first episode psychosis patients. We also demonstrated that brain circuitry alterations are clinically relevant by showing that these pathological signatures can be leveraged for predicting subsequent response to antipsychotic treatment. Interestingly, dopamine D2 receptor blockers alleviate neural abnormalities to some extent. Taken together, it is highly unlikely that the pathogenesis of schizophrenia is uniform, it is more plausible that there may be multiple different etiologies that converge to the behavioral phenotype of schizophrenia. Our data underscore that mechanistically oriented neuroimaging studies must take non-specific factors such as antipsychotic drug exposure or illness chronicity into consideration when interpreting disease signatures, as a clear characterization of primary pathophysiological processes is an imperative prerequisite for rational drug development and for alleviating disease burden in our patients.
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The deficit syndrome is thought to be a more homogenous clinical subgroup within the syndrome of schizophrenia that is characterized by enduring negative symptoms. It is hypothesized that distinct pathophysiological processes underlie the subtypes, where the deficit syndrome reflects an early onset nonprogressive developmental process, and the nondeficit form of the illness is characterized by attenuated neuroplasticity secondary to elevated glutamate levels. We used single-voxel magnetic resonance spectroscopy (PRESS; TE: 30 ms) to measure left frontal white matter neurometabolite levels in 61 antipsychotic-naïve first-episode psychosis patients (39 who did not display deficit features, 22 who did display deficit features, assessed with the Schedule for the Deficit Syndrome) and 59 healthy controls. Metabolite levels were quantified with the LCModel. We used a MANCOVA to determine neurometabolite differences between healthy controls, deficit syndrome patients, and nondeficit patients. We report a significant group difference when all metabolites were considered jointly (F[10,208] = 2.16; P = .02). Post hoc analyses showed that patients presenting without deficit features had higher glutamate levels than patients with deficit features and controls. Patients presenting without deficit features also had significantly higher myoinositol levels than controls; myoinositol levels were trend-level higher in patients presenting with deficit features compared to controls. Our data support the idea that the pathophysiology of patients presenting without deficit features may differ from those presenting with deficit features.
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Transtornos Psicóticos/fisiopatologia , Substância Branca/metabolismo , Adulto , Antipsicóticos/uso terapêutico , Estudos de Casos e Controles , Feminino , Ácido Glutâmico/metabolismo , Humanos , Inositol/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Transtornos Psicóticos/tratamento farmacológico , Adulto JovemRESUMO
Background: Diffusion tensor imaging suggests that white matter alterations are already evident in first episode psychosis patients (FEP) and may become more prominent as the duration of untreated psychosis (DUP) increases. But because the tensor model lacks specificity, it remains unclear how to interpret findings on a biological level. Here, we used a biophysical diffusion model, Neurite Orientation Dispersion and Density Imaging (NODDI), to map microarchitecture in FEP, and to investigate associations between DUP and microarchitectural integrity. Methods: We scanned 78 antipsychotic medication-naïve FEP and 64 healthy controls using a multi-shell diffusion weighted sequence and used the NODDI toolbox to compute neurite density (ND), orientation dispersion index (ODI) and extracellular free water (FW) maps. AFNI's 3dttest++ was used to compare diffusion maps between groups and to perform regression analyses with DUP. Results: We found that ND was decreased in commissural and association fibers but increased in projection fibers in FEP. ODI was largely increased regardless of fiber type, and FW showed a mix of increase in decrease across fiber tracts. We also demonstrated associations between DUP and microarchitecture for all NODDI indices. Conclusions: We demonstrated that complex microarchitecture abnormalities are already evident in antipsychotic-naïve FEP. ND alterations are differentially expressed depending on fiber type, while decreased fiber complexity appears to be a uniform marker of white matter deficit in the illness. Importantly, we identified an empirical link between longer DUP and greater white matter pathology across NODDI indices, underscoring the critical importance of early intervention in this devastating illness.
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BACKGROUND: Converging evidence from neuroimaging and postmortem studies suggests that hippocampal subfields are differentially affected in schizophrenia. Recent studies report dentate gyrus dysfunction in chronic schizophrenia, but the underlying mechanisms remain to be elucidated. Here, we sought to examine if this deficit is already present in first-episode psychosis and if NMDA receptor hypofunction, a putative central pathophysiological mechanism in schizophrenia, experimentally induced by ketamine, would result in a similar abnormality. METHODS: We applied a mnemonic discrimination task selectively taxing pattern separation in two experiments: 1) a group of 23 patients with first-episode psychosis and 23 matched healthy volunteers and 2) a group of 19 healthy volunteers before and during a ketamine challenge (0.27 mg/kg over 10 min, then 0.25 mg/kg/hour for 50 min, 0.01 mL/s). We calculated response bias-corrected pattern separation and recognition scores. We also examined the relationships between task performance and symptom severity as well as ketamine levels. RESULTS: We reported a deficit in pattern separation performance in patients with first-episode psychosis compared with healthy volunteers (p = .04) and in volunteers during the ketamine challenge compared with baseline (p = .003). Pattern recognition was lower in patients with first-episode psychosis than in control subjects (p < .01). Exploratory analyses revealed no correlation between task performance and Repeatable Battery for the Assessment of Neuropsychological Status total scores or positive symptoms in patients with first-episode psychosis or with ketamine serum levels. CONCLUSIONS: We observed a mnemonic discrimination deficit in both datasets. Our findings suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and NMDA receptor hypofunction.
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Antipsychotic medications are the cornerstone of treatment in schizophrenia spectrum disorders. In first-episode psychosis, the recommended time for an antipsychotic medication trial is up to 16 weeks, but the biological correlates of shorter and longer antipsychotic treatment trials in these cohorts remain largely unknown. We enrolled 29 medication-naive first-episode patients (FEP) and 22 matched healthy controls (HC) in this magnetic resonance spectroscopy (MRS) study, examining the levels of combined glutamate and glutamine (commonly referred to as Glx) in the bilateral medial prefrontal cortex (MPFC) with a PRESS sequence (TR/TE = 2000/80 ms) before initiation of antipsychotic treatment, after 6 and 16 weeks of treatment with risperidone. Data were quantified in 18 HC and 20 FEP at baseline, for 19 HC and 15 FEP at week 6, and for 14 HC and 16 FEP at week 16. At baseline, none of the metabolites differed between groups. Metabolite levels did not change after 6 or 16 weeks of treatment in patients. Our data suggest that metabolite levels do not change after 6 or 16 weeks of treatment with risperidone in FEP. It is possible that our choice of sequence parameters and the limited sample size contributed to negative findings reported here. On the other hand, longer follow-up may be needed to detect treatment-related metabolic changes with MRS. In summary, our study adds to the efforts in better understanding glutamatergic neurometabolism in schizophrenia, especially as it relates to antipsychotic exposure.
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Antipsicóticos , Transtornos Psicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , Ácido Glutâmico , Humanos , Transtornos Psicóticos/tratamento farmacológico , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológicoRESUMO
Several imaging studies have attempted to characterize the contribution of glutamatergic dysfunction to functional dysconnectivity of large-scale brain networks using ketamine models. However, findings from BOLD imaging studies are conflicting, in part because the signal stems from a complex interaction between blood flow, blood volume, and oxygen consumption. We used arterial spin labelling imaging to measure regional cerebral blood flow (rCBF) in a group of healthy volunteers during a saline and during a ketamine infusion. We examined changes in rCBF and interregional connectivity patterns, as well as their associations with clinical symptom severity and Glx (glutamate + glutamine) assessed with magnetic resonance spectroscopy. We report a regionally selective pattern of rCBF changes following ketamine administration and complex changes in interregional connectivity patterns. We also found that the increase in rCBF in the bilateral putamen and left hippocampus was positively correlated with ketamine induced clinical symptom severity while anterior cingulate rCBF during the ketamine challenge was negatively correlated with change in hippocampal Glx. Our study adds to the efforts to empirically confirm putative links between an NMDA receptor blockage and dysconnectivity of large-scale brain networks, specifically the salience, executive control and default mode networks, suggesting that a glutamatergic imbalance may contribute to dysconnectivity. Development of glutamatergic compounds that alleviate disease burden, possibly through normalizing glutamate excess related increased rCBF, is direly needed.
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Circulação Cerebrovascular/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Rede Nervosa/efeitos dos fármacos , Putamen/efeitos dos fármacos , Adulto , Feminino , Giro do Cíngulo/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Putamen/diagnóstico por imagem , Adulto JovemRESUMO
Diffusion tensor imaging (DTI) studies show widespread white matter abnormalities in schizophrenia, but it is difficult to directly relate these parameters to biological processes. Neurite orientation dispersion and density imaging (NODDI) is geared toward biophysical characterization of white matter microstructure, but only few studies have leveraged this technique to study white matter alterations. We recruited 42 schizophrenia patients (30 antipsychotic-naïve and 12 currently untreated) and 42 matched controls in this prospective study. We assessed the orientation dispersion index (ODI) and extracellular free water (FW) using single-shell DTI data before and after a 6-week trial of risperidone. Longitudinal data were available for 27 patients. Voxelwise analyses showed significantly increased ODI in the posterior limb of the internal capsule in unmedicated patients (242 voxels; x = -24; y = 6; z = 6; p < 0.01; α < 0.04), but no alterations in FW. Whole brain measures did not reveal alterations in ODI but a 6.3% trend-level increase in FW in unmedicated SZ (t = -1.873; p = 0.07). Baseline ODI was negatively correlated with subsequent response to antipsychotic treatment (r = -0.38; p = 0.049). Here, we demonstrated altered fiber complexity in medication-naïve and unmedicated patients with a schizophrenia spectrum illness. Lesser whole brain fiber uniformity was predictive of poor response to treatment, suggesting this measure may be a clinically relevant biomarker. Interestingly, we found no significant changes in NODDI indices after short-term treatment with risperidone. Our data show that biophysical diffusion models have promise for the in vivo evaluation of brain microstructure in this devastating neuropsychiatric syndrome.
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Encéfalo/diagnóstico por imagem , Neuritos , Esquizofrenia/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adolescente , Adulto , Imagem de Tensor de Difusão , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Schizophrenia is associated with progressive white matter changes, but it is unclear whether antipsychotic medications contribute to these. Our objective was to characterize effects of short-term treatment with risperidone on white matter diffusion indices. METHODS: We recruited 42 patients with schizophrenia (30 never treated and 12 currently untreated) and 42 matched healthy control subjects in this prospective case-control neuroimaging study. Patients received a 6-week trial of risperidone. Using diffusion tensor imaging, we assessed microstructural (fractional anisotropy, mean diffusivity, and radial diffusivity) and macrostructural (radial fiber trophy) white matter integrity deficits in unmedicated patients compared with control subjects and change in white matter integrity in patients before and after antipsychotic treatment (mean risperidone dose at end point was 3.73 ± 1.72 mg). RESULTS: At baseline, fractional anisotropy was decreased in the left medial temporal white matter (cluster extent: 123 voxels; Montreal Neurological Institute peak coordinates: x = -51, y = -44, z = -7; α < .05), and mean diffusivity was increased in the fusiform/lingual gyrus white matter extending to the hippocampal part of the cingulum (cluster extent: 185 voxels; peak coordinates: x = -27, y = -49, z = 2; α < .04) in patients compared with control subjects. Radial diffusivity and macrostructure were not abnormal. None of the diffusion indices showed a significant change after 6 weeks of treatment with both voxelwise and whole-brain white matter analyses. CONCLUSIONS: We demonstrate microstructural white matter integrity abnormalities in the absence of macrostructural impairment in unmedicated patients with primarily early-stage schizophrenia. In our data, we found no significant white matter changes after short-term treatment with risperidone.
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Antipsicóticos/uso terapêutico , Encéfalo/patologia , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Substância Branca/patologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Esquizofrenia/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos dos fármacos , Adulto JovemRESUMO
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). Retraction notice to: "Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggests Dentate Gyrus Pathology Linked to N-Methyl-D-Aspartate Receptor Hypofunction" by Nina Vanessa Kraguljac, Matthew Carle, Michael A. Frölich, Steve Tran, Michael A. Yassa, David Matthew White, Abhishek Reddy, and Adrienne Carol Lahti (Biol Psychiatry Cogn Neurosci Neuroimaging 2018; 3:231-238); https://doi.org/10.1016/j.bpsc.2017.02.005. This article has been retracted at the request of Cameron S. Carter, M.D., Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, with agreement from all authors. The authors discovered an error in the calculation of the response biascorrected pattern recognition score in this article, which has significantly changed the results for experiment 1. Specifically, the authors discovered that the response bias corrected pattern recognition score was erroneously computed as P('old'|target) minus P('old'|lure) rather than P('old'|target) minus P('old'|foil). After re-running statistical analyses with the correct values, the authors found a significant difference in the response biascorrected pattern recognition score in healthy volunteers (HV) compared with first-episode psychosis (FEP) patients (HV: 84.13 ± 10.96; FEP: 63.70 ± 21.83; t = 4.01; p < .01) in experiment 1. This finding is not consistent with the original report, where the authors reported no group differences in bias-corrected pattern recognition scores (originally reported values: t = 0.93, p = .36). The authors again found no significant correlations between pattern completion scores and BPRS total, positive, or negative symptom scores or RBANS scores, consistent with the original report. In experiment 2, bias-corrected pattern recognition scores did not differ between the saline and ketamine conditions (saline: 78.29 ± 28.04; ketamine: 73.59 ± 18.94; t = 0.81; p = 0.43), which is consistent with the original report (originally reported values: t = −0.69, p = .50). Contrary to the original report, task performance during the saline and ketamine infusions was no longer correlated at trend level for pattern recognition. Repeat analyses showed no correlations between pattern recognition scores during the ketamine challenge and BPRS total, positive, and negative symptom scores, or ketamine plasma levels at either time point, consistent with the original report. The authors have verified that bias-corrected pattern separation scores were calculated correctly for both experiments in the initial report. This error affects the abstract, the results, Figure 1, and discussion of the manuscript. The authors voluntarily informed the Journal of this honest error upon its discovery. Because of the extent and nature of the changes to the paper, the editors and authors concluded that, to ensure maximum clarity and transparency, the only course of action was to retract this version of the paper. The authors are revising the paper, which the Journal will re-review and consider further for publication.
Assuntos
Discriminação Psicológica/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Transtornos Psicóticos/psicologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Adulto , Feminino , Hipocampo/efeitos dos fármacos , Humanos , Masculino , Testes Neuropsicológicos , Psicologia do Esquizofrênico , Adulto JovemRESUMO
Since Emil Kraepelin's conceptualization of endogenous psychoses as dementia praecox and manic depression, the separation between primary psychotic disorders and primary affective disorders has been much debated. We conducted a systematic review of case-control studies contrasting magnetic resonance imaging studies in schizophrenia and bipolar disorder. A literature search in PubMed of studies published between January 2005 and December 2016 was conducted, and 50 structural, 29 functional, 7 magnetic resonance spectroscopy, and 8 combined imaging and genetic studies were deemed eligible for systematic review. Structural neuroimaging studies suggest white matter integrity deficits that are consistent across the illnesses, while gray matter reductions appear more widespread in schizophrenia compared to bipolar disorder. Spectroscopy studies in cortical gray matter report evidence of decreased neuronal integrity in both disorders. Functional neuroimaging studies typically report similar functional architecture of brain networks in healthy controls and patients across the psychosis spectrum, but find differential extent of alterations in task related activation and resting state connectivity between illnesses. The very limited imaging-genetic literature suggests a relationship between psychosis risk genes and brain structure, and possible gene by diagnosis interaction effects on functional imaging markers. While the existing literature suggests some shared and some distinct neural markers in schizophrenia and bipolar disorder, it will be imperative to conduct large, well designed, multi-modal neuroimaging studies in medication-naïve first episode patients that will be followed longitudinally over the course of their illness in an effort to advance our understanding of disease mechanisms.
RESUMO
A number of neuroimaging studies have provided evidence in support of the hypothesis that faulty interactions between spatially disparate brain regions underlie the pathophysiology of schizophrenia, but it remains unclear to what degree antipsychotic medications affect these. We hypothesized that the balance between functional integration and segregation of brain networks is impaired in unmedicated patients with schizophrenia, but that it can be partially restored by antipsychotic medications. We included 32 unmedicated patients with schizophrenia (SZ) and 32 matched healthy controls (HC) in this study. We obtained resting-state scans while unmedicated, and again after 6 weeks of treatment with risperidone to assess functional integration and functional segregation of brain networks using graph theoretical measures. Compared with HC, unmedicated SZ showed reduced global efficiency and increased clustering coefficients. This pattern of aberrant functional network integration and segregation was modulated with antipsychotic medications, but only in those who responded to treatment. Our work lends support to the concept of schizophrenia as a dysconnectivity syndrome, and suggests that faulty brain network topology in schizophrenia is modulated by antipsychotic medication as a function of treatment response.
RESUMO
OBJECTIVE: To describe abnormalities in large scale functional networks in unmedicated patients with schizophrenia and to examine effects of risperidone on networks. MATERIAL AND METHODS: 34 unmedicated patients with schizophrenia and 34 matched healthy controls were enrolled in this longitudinal study. We collected resting state functional MRI data with a 3T scanner at baseline and six weeks after they were started on risperidone. In addition, a group of 19 healthy controls were scanned twice six weeks apart. Four large scale networks, the dorsal attention network, executive control network, salience network, and default mode network were identified with seed based functional connectivity analyses. Group differences in connectivity, as well as changes in connectivity over time, were assessed on the group's participant level functional connectivity maps. RESULTS: In unmedicated patients with schizophrenia we found resting state connectivity to be increased in the dorsal attention network, executive control network, and salience network relative to control participants, but not the default mode network. Dysconnectivity was attenuated after six weeks of treatment only in the dorsal attention network. Baseline connectivity in this network was also related to clinical response at six weeks of treatment with risperidone. CONCLUSIONS: Our results demonstrate abnormalities in large scale functional networks in patients with schizophrenia that are modulated by risperidone only to a certain extent, underscoring the dire need for development of novel antipsychotic medications that have the ability to alleviate symptoms through attenuation of dysconnectivity.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Risperidona/farmacologia , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Adulto , Atenção/fisiologia , Mapeamento Encefálico , Função Executiva/fisiologia , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologiaRESUMO
To better characterize hippocampal pathophysiology in schizophrenia, we conducted a longitudinal study evaluating hippocampal functional connectivity during resting state, using seeds prescribed in its anterior and posterior regions. We enrolled 34 unmedicated patients with schizophrenia or schizoaffective disorder (SZ) and 34 matched healthy controls. SZ were scanned while off medication, then were treated with risperidone for 6 weeks and re-scanned (n = 22). Group differences in connectivity, as well as changes in connectivity over time, were assessed on the group's participant level functional connectivity maps. We found significant dysconnectivity with anterior and posterior hippocampal seeds in unmedicated SZ. Baseline connectivity between the hippocampus and anterior cingulate cortex, caudate nucleus, auditory cortex and calcarine sulcus in SZ predicted subsequent response to antipsychotic medications. These same regions demonstrated changes over the 6-week treatment trial that were correlated with symptomatic improvement. Our findings implicate several neural networks relevant to clinical improvement with antipsychotic medications.