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BACKGROUND: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels. METHODS: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength. RESULTS: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18-0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21-0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05-0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = -0.40; 95% CIs: -0.62 to -0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38-1.01; Glu: g = 0.63; 95% CIs: 0.31-0.94) while MCC Glu levels were decreased in the patient group except TRS (g = -0.17; 95% CIs: -0.33 to -0.01). CONCLUSIONS: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.
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Esquizofrenia , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Espectroscopia de Prótons por Ressonância Magnética/métodos , Esquizofrenia/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-ß (Aß) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand, [11C]PBB3, and an Aß radioligand, [11C]PiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical [11C]PBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences.
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Transtorno Depressivo Maior , Idoso , Peptídeos beta-Amiloides , Compostos de Anilina , Transtorno Depressivo Maior/diagnóstico por imagem , Humanos , Ligantes , Tomografia por Emissão de Pósitrons , Proteínas tauRESUMO
BACKGROUND: Abnormalities in the anterior cingulate cortex (ACC) are thought to play an important role in the pathophysiology of schizophrenia. Given regional variations in ACC structure, the present study aimed to examine ACC structural subdivisions and their relationships to treatment resistance and glutamatergic levels in schizophrenia. METHODS: This study included 100 patients with schizophrenia and 52 healthy controls from 2 cohorts. We applied non-negative matrix factorization to identify accurate and stable spatial components of ACC structure. Between groups, we compared ACC structural indices in each spatial component based on treatment resistance or response and tested relationships with ACC glutamate + glutamine levels. RESULTS: We detected reductions in cortical thickness and increases in mean diffusivity in the spatial components on the surface of the cingulate sulcus, especially in patients with treatment-resistant and clozapine-resistant schizophrenia. Notably, mean diffusivity in these components was higher in patients who did not respond to clozapine compared to those who did. Furthermore, these ACC structural alterations were related to elevated ACC glutamate + glutamine levels but not related to symptomatology or antipsychotic dose. LIMITATIONS: Sample sizes, cross-sectional findings and mixed antipsychotic status were limitations of this study. CONCLUSION: This study identified reproducible abnormalities in ACC structures in patients with treatment-resistant and clozapine-resistant schizophrenia. Given that these spatial components play a role in inhibitory control, the present study strengthens the notion that glutamate-related disinhibition is a common biological feature of treatment resistance in schizophrenia.
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Antipsicóticos , Clozapina , Esquizofrenia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Clozapina/farmacologia , Clozapina/uso terapêutico , Estudos Transversais , Ácido Glutâmico , Glutamina , Giro do Cíngulo/diagnóstico por imagem , Humanos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológicoRESUMO
Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (1H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR "magnetic resonance spectroscopy"). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = -0.38; 95% CI, -0.69 to -0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = -0.50; 95% CI, -0.80 to -0.20), but not in unmedicated patients (SMD = -0.27; 95% CI, -0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.
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Ácido Glutâmico/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Prótons por Ressonância Magnética/métodos , Adolescente , Adulto , Idoso , Ácido Aspártico/metabolismo , Depressão/diagnóstico por imagem , Depressão/metabolismo , Depressão/fisiopatologia , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Feminino , Ácido Glutâmico/análise , Glutamina/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Transmissão SinápticaRESUMO
OBJECTIVE: To identify important clinical or imaging features predictive of an individual's response to electroconvulsive therapy (ECT) by utilizing a machine learning approach. METHODS: Twenty-seven depressed patients who received ECT were recruited. Clinical demographics and pretreatment structural magnetic resonance imaging (MRI) data were used as candidate features to build models to predict remission and post-ECT Hamilton Depression Rating Scale scores. Support vector machine and support vector regression with elastic-net regularization were used to build models using (i) only clinical features, (ii) only MRI features, and (iii) both clinical and MRI features. Consistently selected features across all individuals were identified through leave-one-out cross-validation. RESULTS: Compared with models that include only clinical variables, the models including MRI data improved the prediction of ECT remission: the prediction accuracy improved from 70% to 93%. Features selected consistently across all individuals included volumes in the gyrus rectus, the right anterior lateral temporal lobe, the cuneus, and the third ventricle, as well as 2 clinical features: psychotic features and family history of mood disorder. CONCLUSIONS: Pretreatment structural MRI data improved the individual predictive accuracy of ECT remission, and only a small subset of features was important for prediction.
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Encéfalo/diagnóstico por imagem , Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia , Aprendizado de Máquina , Imageamento por Ressonância Magnética/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Indução de RemissãoRESUMO
OBJECTIVE: The degree and quality of resilience in patients with depression have never been investigated in the context of remission status, spirituality/religiosity, and family members' resilience levels, which was addressed in this study. METHODS: This cross-sectional study recruited Japanese outpatients with depressive disorder according to ICD-10 and cohabitant family members who were free from psychiatric diagnoses. Resilience was assessed using the 25-item Resilience Scale (RS). Other assessments included the Montgomery-Asberg Depression Rating Scale (MADRS); the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT) and Kasen et al.'s (2012) scale for spirituality/religiosity; and the Rosenberg Self-Esteem Scale (RSES). RESULTS: One hundred outpatients with depression (mean±SD age, 50.8±14.5years; 44 men; MADRS total score 9.8±9.0) and 36 healthy family members (mean±SD age, 56.5±15.0years; 18 men) were included. Symptom severity, attendance at religious/spiritual services, and self-esteem were significantly associated with RS scores in the patient group. RS total scores were significantly higher in remitted patients compared to non-remitted patients (mean±SD, 112.3±17.1 vs. 84.8±27.7, p<0.001). No correlation was found in RS total scores between patients and their family members (p=0.265), regardless of patients' remission status. CONCLUSIONS: Resilience may be influenced by individual characteristics rather than familial environment; furthermore, self-esteem or spirituality/religiosity may represent reinforcing elements. While caution is necessary in extrapolating these findings to other patient populations, our results suggest that resilience may be considered a state marker in depression.
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Transtorno Depressivo/psicologia , Família/psicologia , Resiliência Psicológica , Espiritualidade , Adulto , Estudos Transversais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais/psicologia , Religião e Psicologia , AutoimagemRESUMO
BACKGROUND AND HYPOTHESIS: Schizophrenia is associated with widespread cortical thinning and abnormality in the structural covariance network, which may reflect connectome alterations due to treatment effect or disease progression. Notably, patients with treatment-resistant schizophrenia (TRS) have stronger and more widespread cortical thinning, but it remains unclear whether structural covariance is associated with treatment response in schizophrenia. STUDY DESIGN: We organized a multicenter magnetic resonance imaging study to assess structural covariance in a large population of TRS and non-TRS, who had been resistant and responsive to non-clozapine antipsychotics, respectively. Whole-brain structural covariance for cortical thickness was assessed in 102 patients with TRS, 77 patients with non-TRS, and 79 healthy controls (HC). Network-based statistics were used to examine the difference in structural covariance networks among the 3 groups. Moreover, the relationship between altered individual differentiated structural covariance and clinico-demographics was also explored. STUDY RESULTS: Patients with non-TRS exhibited greater structural covariance compared with HC, mainly in the fronto-temporal and fronto-occipital regions, while there were no significant differences in structural covariance between TRS and non-TRS or HC. Higher individual differentiated structural covariance was associated with lower general scores of the Positive and Negative Syndrome Scale in the non-TRS group, but not in the TRS group. CONCLUSIONS: These findings suggest that reconfiguration of brain networks via coordinated cortical thinning is related to treatment response in schizophrenia. Further longitudinal studies are warranted to confirm if greater structural covariance could serve as a marker for treatment response in this disease.
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Antipsicóticos , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Afinamento Cortical Cerebral , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
Quantitative susceptibility mapping is a magnetic resonance imaging technique that measures brain tissues' magnetic susceptibility, including iron deposition and myelination. This study examines the relationship between subcortical volume and magnetic susceptibility and determines specific differences in these measures among patients with major depressive disorder (MDD), patients with schizophrenia, and healthy controls (HCs). This was a cross-sectional study. Sex- and age- matched patients with MDD (n = 49), patients with schizophrenia (n = 24), and HCs (n = 50) were included. Magnetic resonance imaging was conducted using quantitative susceptibility mapping and T1-weighted imaging to measure subcortical susceptibility and volume. The acquired brain measurements were compared among groups using analyses of variance and post hoc comparisons. Finally, a general linear model examined the susceptibility-volume relationship. Significant group-level differences were found in the magnetic susceptibility of the nucleus accumbens and amygdala (p = 0.045). Post-hoc analyses indicated that the magnetic susceptibility of the nucleus accumbens and amygdala for the MDD group was significantly higher than that for the HC group (p = 0.0054, p = 0.0065, respectively). However, no significant differences in subcortical volume were found between the groups. The general linear model indicated a significant interaction between group and volume for the nucleus accumbens in MDD group but not schizophrenia or HC groups. This study showed susceptibility alterations in the nucleus accumbens and amygdala in MDD patients. A significant relationship was observed between subcortical susceptibility and volume in the MDD group's nucleus accumbens, which indicated abnormalities in myelination and the dopaminergic system related to iron deposition.
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Transtorno Depressivo Maior , Esquizofrenia , Humanos , Transtorno Depressivo Maior/patologia , Esquizofrenia/patologia , Estudos Transversais , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , FerroRESUMO
BACKGROUND AND HYPOTHESIS: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. STUDY DESIGN: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis. STUDY RESULTS: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (Pâ =â .001). The GP-CX type presented earlier stages than the pure CX type (Pâ =â .009). CONCLUSIONS: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.
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Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/complicações , Estudos Transversais , Afinamento Cortical Cerebral/patologia , Imageamento por Ressonância Magnética , Lobo Temporal/patologia , Progressão da Doença , Hipertrofia/complicações , Hipertrofia/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
Accumulating evidence indicates that pathophysiology of schizophrenia involves abnormalities in the dopamine and glutamatergic neuronal systems. Antipsychotic medications are currently used to normalize dopaminergic function for schizophrenia. However, approximately 30 % of the patients have no response to antipsychotic medications, which is classified as treatment-resistant schizophrenia (TRS). Furthermore, dopamine and glutamate levels in the neural basis have been reported to differ between TRS and non-TRS. In this study, we assumed that these differences may affect music rhythm perception and production abilities between the two groups. We examined fifty-seven schizophrenia (26 TRS, 31 non-TRS) and thirty-one healthy controls (HCs) by using the Harvard Beat Assessment Test (H-BAT). As a result, we found that rhythm production was worse in patients with TRS compared to patients with non-TRS and HCs, while no difference was observed between patients with non-TRS and HCs. In addition, rhythm perception and production abilities were impaired in the whole patient group compared with HCs. Furthermore, in the patient group, the deficits were correlated with cognitive impairments. Collectively, these results suggest that patients with schizophrenia may have rhythm processing deficits, with particular a rhythm production problem in the TRS group.
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Antipsicóticos , Música , Esquizofrenia , Humanos , Antipsicóticos/uso terapêutico , Dopamina , PercepçãoRESUMO
Introduction: Glutamatergic neurometabolites play important roles in the basal ganglia, a hub of the brain networks involved in musical rhythm processing. We aimed to investigate the relationship between rhythm processing abilities and glutamatergic neurometabolites in the caudate. Methods: We aquired Glutamatergic function in healthy individuals employing proton magnetic resonance spectroscopy. We targeted the right caudate and the dorsal anterior cingulate cortex (dACC) as a control region. Rhythm processing ability was assessed by the Harvard Beat Assessment Test (H-BAT). Results: We found negative correlations between the production part of the Beat Saliency Test in the H-BAT and glutamate and glutamine levels in the caudate (r = -0.693, p = 0.002) whereas there was no such association in the dACC. Conclusion: These results suggest that higher glutamatergic neurometabolite levels in the caudate may contribute to rhythm processing, especially the ability to produce meter in music precisely.
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BACKGROUND AND HYPOTHESIS: Phosphodiesterase 10A (PDE10A) is a highly expressed enzyme in the basal ganglia, where cortical glutamatergic and midbrain dopaminergic inputs are integrated. Therapeutic PDE10A inhibition effects on schizophrenia have been reported previously, but the status of this molecule in the living patients with schizophrenia remains elusive. Therefore, this study aimed to investigate the central PDE10A status in patients with schizophrenia and examine its relationship with psychopathology, cognition, and corticostriatal glutamate levels. STUDY DESIGN: This study included 27 patients with schizophrenia, with 5 antipsychotic-free cases, and 27 healthy controls. Positron emission tomography with [18F]MNI-659, a specific PDE10A radioligand, was employed to quantify PDE10A availability by measuring non-displaceable binding potential (BPND) of the ligand in the limbic, executive, and sensorimotor striatal functional subregions, and in the pallidum. BPND estimates were compared between patients and controls while controlling for age and gender. BPND correlations were examined with behavioral and clinical measures, along with regional glutamate levels quantified by the magnetic resonance spectroscopy. STUDY RESULTS: Multivariate analysis of covariance demonstrated a significant main effect of diagnosis on BPND (p = .03). A posthoc test showed a trend-level higher sensorimotor striatal BPND in patients, although it did not survive multiple comparison corrections. BPND in controls in this subregion was significantly and negatively correlated with the Tower of London scores, a cognitive subtest. Striatal or dorsolateral prefrontal glutamate levels did not correlate significantly with BPND in either group. CONCLUSIONS: The results suggest altered striatal PDE10A availability and associated local neural dysfunctions in patients with schizophrenia.
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Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagem , Diester Fosfórico Hidrolases/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Gânglios da Base , GlutamatosRESUMO
BACKGROUND: Regular visit to psychiatric clinic is essential for successful treatment of any psychiatric condition including attention-deficit/hyperactivity disorder (AD/HD). However, cancellation of outpatient appointments in patients with AD/HD, which represents a significant medical loss, has not been systematically investigated to our knowledge. METHODS: A systematic chart review was conducted for patients visiting the Shimada Ryoiku medical Center for Challenged Children in Japan at the age of ≤15 years from January to December 2013. The primary outcome measure was the cancellation rate, defined as the number of missed visits divided by the number of scheduled visits. The cancellation rates during 24 months after the first visit were compared between outpatients with AD/HD and other psychiatric disorders, including pervasive developmental disorders (PDD), and developmental coordination disorders and/or communication disorders (DCD-CD). A generalized linear model with binomial distribution was used to examine factors associated with cancellation rates exclusively in the AD/HD group. RESULTS: We included 589 patients (mean ± SD age, 5.6 ± 3.4 years; 432 males) in the analysis. The cancellation rate in patients with AD/HD was 12.3% (95% confidence interval [CI]: 10.0-15.1), which was significantly higher than in those with PDD (5.6%, 95% CI: 3.8-8.3) and DCD-CD (5.3%, 95% CI: 3.6-7.8). Prescriptions of osmotic-release oral system-methylphenidate (OROS-MPH) and antipsychotics were associated with fewer cancellations in AD/HD patients (odds ratios: 0.61, 95% CI: 0.39-0.95 and 0.49, 95% CI: 0.25-0.95, respectively), although these significances did not find in the subgroup analysis including only patients with ≥ 6 years old. CONCLUSIONS: Patients with AD/HD were more likely to miss appointments compared to those with other psychiatric disorders. The impact of AD/HD medications as well as potential psychiatric symptoms of their parents or caregivers on appointment cancellations needs to be evaluated in more detail in future investigations.
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Assistência Ambulatorial/psicologia , Assistência Ambulatorial/estatística & dados numéricos , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Pacientes Ambulatoriais/psicologia , Pacientes Ambulatoriais/estatística & dados numéricos , Feminino , Humanos , Japão , MasculinoRESUMO
Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that enables the investigation of cortical excitability in the human brain. Paired-pulse TMS paradigms include short- and long-interval intracortical inhibition (SICI/LICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI), which can assess neurophysiological functions of GABAergic, glutamatergic, and cholinergic neural circuits, respectively. We conducted the first systematic review and meta-analysis to compare these TMS indices among patients with AD, mild cognitive impairment (MCI), and healthy controls (HC). Our meta-analyses indicated that RMT, SAI, SICI, and LICI were significantly lower in patients with AD, while ICF did not show a difference in patients with AD compared with HC. In patients with MCI, RMT and SAI were significantly lower than in HC. In conclusion, motor cortical excitability was increased, while cholinergic function was decreased in AD and MCI in comparison with HC and patients with AD had decreased GABAergic and glutamatergic functions compared with HC. Our results warrant further studies to differentiate AD, MCI, and HC, employing multimodal TMS neurophysiology.
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Doença de Alzheimer , Disfunção Cognitiva , Biomarcadores , Potencial Evocado Motor , Humanos , Inibição Neural , Neurofisiologia , Estimulação Magnética TranscranianaRESUMO
BACKGROUND: One-third of patients with schizophrenia are treatment-resistant to non-clozapine antipsychotics (TRS), while the rest respond (NTRS). Examining whether TRS and NTRS represent different pathophysiologies is an important step toward precision medicine. METHODS: Focusing on cortical thickness (CT), we analyzed international multi-site cross-sectional datasets of magnetic resonance imaging comprising 110 patients with schizophrenia (NTRS = 46, TRS = 64) and 52 healthy controls (HCs). We utilized a logistic regression with L1-norm regularization to find brain regions related to either NTRS or TRS. We conducted nested 10-fold cross-validation and computed the accuracy and area under the curve (AUC). Then, we applied the NTRS classifier to patients with TRS, and vice versa. RESULTS: Patients with NTRS and TRS were classified from HCs with 65% and 78% accuracies and with the AUC of 0.69 and 0.85 (p = 0.014 and < 0.001, corrected), respectively. The left planum temporale (PT) and left anterior insula/inferior frontal gyrus (IFG) contributed to both NTRS and TRS classifiers. The left supramarginal gyrus only contributed to NTRS and right superior temporal sulcus and right lateral orbitofrontal cortex only to the TRS. The NTRS classifiers successfully distinguished those with TRS from HCs with the AUC of 0.78 (p < 0.001), while the TRS classifiers classified those with NTRS from HCs with the AUC of 0.69 (p = 0.015). CONCLUSION: Both NTRS and TRS could be distinguished from HCs on the basis of CT. The CT pathological basis of NTRS and TRS has commonalities, and TRS presents unique CT features.
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Antipsicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , Encéfalo/diagnóstico por imagem , Estudos Transversais , Humanos , Imageamento por Ressonância Magnética , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológicoRESUMO
AIM: It is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity. METHODS: This study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6-week double-blind, placebo-controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2. RESULTS: Response was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R2 : .51, .42 and .55, .54, respectively). CONCLUSION: Early improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity.
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Antipsicóticos/uso terapêutico , Dibenzocicloeptenos/uso terapêutico , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Método Simples-Cego , Fatores de Tempo , Resultado do TratamentoRESUMO
Delay discounting (DD) represents decreased subjective value for delayed reward relative to the same reward at present. The concept of DD has been applied for pathophysiology of addiction and psychiatric disorders. However, the detailed neuroimaging correlates of DD underlying pathophysiology still remain unclear. Thus, we conducted a systematic review to investigate neural correlates of DD on magnetic resonance imaging studies among addiction and psychiatric disorders. Specific search terms were set on PubMed to identify relevant articles. Initial search identified 551 records and 31 studies met the inclusion criteria. The present review revealed that greater DD was correlated with increased activity in areas related to reward evaluation and prediction as well as decreased activity in areas related to cognitive control. Healthy controls showed smaller changes in activities of these areas associated with DD when compared to patient groups. As the neural basis related to DD, three neural networks have been proposed that are associated with the actions of short-term interests and long-term benefits. Among the three potential neural networks on DD, the first one included the ventromedial prefrontal cortex and ventral striatum and implicated in evaluating reward values, the second network included the anterior cingulate cortex and linked to cognitive control, and the third network included the middle temporal gyrus and was involved in predictions and affection. This review generated consistent findings on the neural basis of DD among patients with addiction and psychiatric disorders, which may represent the pathophysiology related to DD and impulsivity of mental illness.
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Comportamento Aditivo/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Desvalorização pelo Atraso/fisiologia , Imageamento por Ressonância Magnética/métodos , Transtornos Mentais/diagnóstico por imagem , Comportamento Aditivo/psicologia , Humanos , Transtornos Mentais/psicologiaRESUMO
Background: The neural basis of treatment-resistant schizophrenia (TRS) remains unclear. Previous neuroimaging studies suggest that aberrant connectivity between the anterior cingulate cortex (ACC) and default mode network (DMN) may play a key role in the pathophysiology of TRS. Thus, we aimed to examine the connectivity between the ACC and posterior cingulate cortex (PCC), a hub of the DMN, computing isolated effective coherence (iCoh), which represents causal effective connectivity. Methods: Resting-state electroencephalogram with 19 channels was acquired from seventeen patients with TRS and thirty patients with non-TRS (nTRS). The iCoh values between the PCC and ACC were calculated using sLORETA software. We conducted four-way analyses of variance (ANOVAs) for iCoh values with group as a between-subject factor and frequency, directionality, and laterality as within-subject factors and post-hoc independent t-tests. Results: The ANOVA and post-hoc t-tests for the iCoh ratio of directionality from PCC to ACC showed significant findings in delta (t45 = 7.659, p = 0.008) and theta (t45 = 8.066, p = 0.007) bands in the left side (TRS < nTRS). Conclusion: Left delta and theta PCC and ACC iCoh ratio may represent a neurophysiological basis of TRS. Given the preliminary nature of this study, these results warrant further study to confirm the importance of iCoh as a clinical indicator for treatment-resistance.
RESUMO
Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.
Assuntos
Antipsicóticos/uso terapêutico , Ácido Glutâmico/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Índice de Gravidade de Doença , Adulto , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológicoRESUMO
Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p < .05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.