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BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has recently gained relevance in treating different psychiatric disorders. Limited evidence suggests that the beneficial effects of rTMS on psychopathology could be at least partly mediated through changes in inflammatory response. This systematic review summarizes the literature on whether rTMS can modulate inflammatory markers and thus positively influence the course of psychiatric illnesses. MATERIALS AND METHODS: A systematic review of rTMS and inflammatory markers in psychiatric diseases was conducted according to PRISMA guidelines. Information on the association between rTMS treatment response and changes of inflammatory markers was extracted. The quality of the studies was assessed using the National Heart, Lung, and Blood Institute for human studies and the Systematic Review Center for Laboratory Animal Experimentation for animal studies. RESULTS: This review includes 17 studies (2 animal and 15 human studies) on the relationship between rTMS treatment response and changes of inflammatory markers. Positive changes in microglial activity and anti-inflammatory effects were associated with behavioral improvement in animal models of depression. However, these findings have not been consistently replicated in human studies focusing on treatment-resistant depression. While several studies reported rTMS-induced alterations in peripheral inflammatory markers, only two could demonstrate their association to clinical treatment response. Notably, most studies showed poor or moderate quality in the bias assessment. CONCLUSIONS: While certain human studies suggest an association between rTMS-induced anti-inflammatory effects and improvement in psychopathology, heterogeneity, and underpowered analyses constrain the generalizability of these results. The discrepancy between animal and human findings highlights the need for larger, standardized human studies. TRIAL REGISTRATION: (PROSPERO Registration: CRD42023492732).
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Silencing of dopamine transporter (DAT), a main controlling factor of dopaminergic signaling, results in biochemical and behavioral features characteristic for neuropsychiatric diseases with presumed hyperdopaminergia including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and obsessive-compulsive disorder (OCD). Investigation of DAT silencing thus provides a transdiagnostic approach towards a systems-level understanding of common underlying pathways. Using a high-field multimodal imaging approach and a highly sensitive cryogenic coil, we integrated structural, functional and metabolic investigations in tandem with behavioral assessments on a newly developed preclinical rat model, comparing DAT homozygous knockout (DAT-KO, N = 14), heterozygous knockout (N = 8) and wild-type male rats (N = 14). We identified spatially distributed structural and functional brain alterations encompassing motor, limbic and associative loops that demonstrated strong behavioral relevance and were highly consistent across imaging modalities. DAT-KO rats manifested pronounced volume loss in the dorsal striatum, negatively correlating with cerebellar volume increase. These alterations were associated with hyperlocomotion, repetitive behavior and loss of efficient functional small-world organization. Further, prefrontal and midbrain regions manifested opposite changes in functional connectivity and local network topology. These prefrontal disturbances were corroborated by elevated myo-inositol levels and increased volume. To conclude, our imaging genetics approach provides multimodal evidence for prefrontal-midbrain decoupling and striato-cerebellar neuroplastic compensation as two key features of constitutive DAT blockade, proposing them as transdiagnostic mechanisms of hyperdopaminergia. Thus, our study connects developmental DAT blockade to systems-level brain changes, underlying impaired action inhibition control and resulting in motor hyperactivity and compulsive-like features relevant for ADHD, schizophrenia and OCD.
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Trastorno por Déficit de Atención con Hiperactividad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Animales , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Encéfalo/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Hipercinesia/metabolismo , Masculino , Mesencéfalo/metabolismo , RatasRESUMEN
Dysfunctions of the thyroid hormone (TH) transporting monocarboxylate transporter MCT8 lead to a complex X-linked syndrome with abnormal serum TH concentrations and prominent neuropsychiatric symptoms (Allan-Herndon-Dudley syndrome, AHDS). The key features of AHDS are replicated in double knockout mice lacking MCT8 and organic anion transporting protein OATP1C1 (Mct8/Oatp1c1 DKO). In this study, we characterize impairments of brain structure and function in Mct8/Oatp1c1 DKO mice using multimodal magnetic resonance imaging (MRI) and assess the potential of the TH analogue 3,3',5-triiodothyroacetic acid (TRIAC) to rescue this phenotype. Structural and functional MRI were performed in 11-weeks-old male Mct8/Oatp1c1 DKO mice (N = 10), wild type controls (N = 7) and Mct8/Oatp1c1 DKO mice (N = 13) that were injected with TRIAC (400 ng/g bw s.c.) daily during the first three postnatal weeks. Grey and white matter volume were broadly reduced in Mct8/Oatp1c1 DKO mice. TRIAC treatment could significantly improve white matter thinning but did not affect grey matter loss. Network-based statistic showed a wide-spread increase of functional connectivity, while graph analysis revealed an impairment of small-worldness and whole-brain segregation in Mct8/Oatp1c1 DKO mice. Both functional deficits could be substantially ameliorated by TRIAC treatment. Our study demonstrates prominent structural and functional brain alterations in Mct8/Oatp1c1 DKO mice that may underlie the psychomotor deficiencies in AHDS. Additionally, we provide preclinical evidence that early-life TRIAC treatment improves white matter loss and brain network dysfunctions associated with TH transporter deficiency.
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Discapacidad Intelectual Ligada al Cromosoma X , Simportadores , Sustancia Blanca , Animales , Masculino , Ratones , Sustancia Blanca/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Hormonas Tiroideas/metabolismo , Atrofia Muscular/metabolismo , Ratones Noqueados , Discapacidad Intelectual Ligada al Cromosoma X/tratamiento farmacológico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Simportadores/genética , Simportadores/metabolismoRESUMEN
Copy number variations (CNV) involving multiple genes are ideal models to study polygenic neuropsychiatric disorders. Since 22q11.2 deletion is regarded as the most important single genetic risk factor for developing schizophrenia, characterizing the effects of this CNV on neural networks offers a unique avenue towards delineating polygenic interactions conferring risk for the disorder. We used a Df(h22q11)/+ mouse model of human 22q11.2 deletion to dissect gene expression patterns that would spatially overlap with differential resting-state functional connectivity (FC) patterns in this model (N = 12 Df(h22q11)/+ mice, N = 10 littermate controls). To confirm the translational relevance of our findings, we analyzed tissue samples from schizophrenia patients and healthy controls using machine learning to explore whether identified genes were co-expressed in humans. Additionally, we employed the STRING protein-protein interaction database to identify potential interactions between genes spatially associated with hypo- or hyper-FC. We found significant associations between differential resting-state connectivity and spatial gene expression patterns for both hypo- and hyper-FC. Two genes, Comt and Trmt2a, were consistently over-expressed across all networks. An analysis of human datasets pointed to a disrupted co-expression of these two genes in the brain in schizophrenia patients, but not in healthy controls. Our findings suggest that COMT and TRMT2A form a core genetic component implicated in differential resting-state connectivity patterns in the 22q11.2 deletion. A disruption of their co-expression in schizophrenia patients points out a prospective cause for the aberrance of brain networks communication in 22q11.2 deletion syndrome on a molecular level.
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Catecol O-Metiltransferasa/genética , Síndrome de DiGeorge/genética , Expresión Génica , ARNt Metiltransferasas/genética , Animales , Deleción Cromosómica , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Esquizofrenia/genéticaRESUMEN
Alterations in the structural connectome of schizophrenia patients have been widely characterized, but the mechanisms remain largely unknown. Generative network models have recently been introduced as a tool to test the biological underpinnings of altered brain network formation. We evaluated different generative network models in healthy controls (n=152), schizophrenia patients (n=66), and their unaffected first-degree relatives (n=32), and we identified spatial and topological factors contributing to network formation. We further investigated how these factors relate to cognition and to polygenic risk for schizophrenia. Our data show that among the four tested classes of generative network models, structural brain networks were optimally accounted for by a two-factor model combining spatial constraints and topological neighborhood structure. The same wiring model explained brain network formation across study groups. However, relatives and schizophrenia patients exhibited significantly lower spatial constraints and lower topological facilitation compared to healthy controls. Further exploratory analyses point to potential associations of the model parameter reflecting spatial constraints with the polygenic risk for schizophrenia and cognitive performance. Our results identify spatial constraints and local topological structure as two interrelated mechanisms contributing to regular brain network formation as well as altered connectomes in schizophrenia and healthy individuals at familial risk for schizophrenia. On an exploratory level, our data further point to the potential relevance of spatial constraints for the genetic risk for schizophrenia and general cognitive functioning, thereby encouraging future studies in following up on these observations to gain further insights into the biological basis and behavioral relevance of model parameters.
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Encéfalo/diagnóstico por imagen , Familia , Esquizofrenia/diagnóstico por imagen , Adulto , Encéfalo/fisiopatología , Estudios de Casos y Controles , Conectoma , Imagen de Difusión Tensora , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Pruebas Neuropsicológicas , Análisis de Componente Principal , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Adulto JovenRESUMEN
INTRODUCTION: A burst suppression pattern in the electroencephalogram represents a down-regulated brain state, which also occurs in the postictal phase of electroconvulsive therapy (ECT). Suppressive actions of the brain to terminate the seizure are thought to be necessary for the efficacy of ECT. On the other hand, recent studies showed an association of burst suppression in general anesthesia or sedation with (postprocedural) cognitive complications. METHODS: We retrospectively examined the length of postictal burst suppression and reorientation time in 49 ECT sessions of 25 consecutive patients. Burst suppression duration was determined by bispectral index monitoring and defined as the time with a bispectral index value of less than 20%. The association between duration of burst suppression and reorientation time was analyzed with multivariate logistic and linear regression analysis controlling for several covariates. RESULTS: The reorientation time showed a statistically significant association with the duration of burst suppression, but with no other variable. Longer phase of postictal burst suppression predicted longer reorientation time in the recovery room (P = 0.046). CONCLUSIONS: The association between the duration of postictal burst suppression and reorientation time after ECT in this sample suggests that (not only the efficacy but also the) cognitive adverse effects of ECT might be related to the extent of postictal central inhibition after the termination of the seizure.
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Terapia Electroconvulsiva , Anestesia General , Terapia Electroconvulsiva/efectos adversos , Electroencefalografía , Humanos , Estudios Retrospectivos , ConvulsionesAsunto(s)
Antipsicóticos , Clozapina , Humanos , Clozapina/efectos adversos , Orosomucoide , Antipsicóticos/efectos adversosRESUMEN
Background: Neuroinflammatory processes in depression are associated with treatment resistance to conventional antidepressants. Ketamine is an effective new therapeutic option for treatment-resistant depression (TRD). Its well-established immunomodulatory properties are hypothesized to mediate its antidepressant effect. In this context, higher levels of inflammation may predict a better treatment response. However, conclusive evidence for this hypothesis is lacking. We thus investigated whether standard peripheral inflammatory cell markers and C-reactive protein (CRP) levels could predict symptom improvement during intravenous ketamine therapy in TRD patients. Methods: 27 participants with TRD were treated with six weight-adjusted intravenous ketamine infusions (0.5 mg/kg bodyweight) over three weeks. Baseline assessments included CRP, absolute monocyte count (AMC), and absolute neutrophil count (ANC). Depression severity was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (D1), after the first (D3) and before the last ketamine infusion (D18). Raters were blinded for the baseline laboratory assessments. Results: 13 participants responded to ketamine treatment, and 8 participants partially responded. Baseline AMC showed a strong negative correlation with MADRS change at D3 (r=-0.57, p=0.002) and at D18 (r =-0.48, p=0.010), indicating that a high baseline AMC was associated with greater symptom improvement. A generalized linear model confirmed the association of baseline AMC with symptom improvement during ketamine treatment when additionally accounting for age, sex, and body mass index. Specifically, baseline AMC demonstrated predictive value to discriminate responders and partial responders from non-responders, but lacked discriminative ability between partial responders and responders. Baseline ANC correlated with the MADRS changes at D3 (r=-0.39, p=0.046), while CRP values did not correlate at all. Conclusions: Our prospective single-arm open-label observational study demonstrated that baseline AMC reliably predicted symptom improvement during intravenous ketamine treatment in TRD patients. AMC could therefore serve as a simple and easily accessible marker for symptom improvement during ketamine therapy in daily clinical practice. Future studies with larger sample sizes and a more detailed longitudinal assessment of AMC subtypes are needed to better understand the specific relationship between monocytes and the neuromodulatory effects of ketamine.
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Social recognition is essential for the formation of social structures. Many times, recognition comes with lesser exploration of familiar animals. This lesser exploration has led to the assumption that recognition may be a habituation memory. The underlying memory mechanisms and the thereby acquired cortical representations of familiar mice have remained largely unknown, however. Here, we introduce an approach directly examining the recognition process from volatile body odors among male mice. We show that volatile body odors emitted by mice are sufficient to identify individuals and that more salience is assigned to familiar mice. Familiarity is encoded by reinforced population responses in two olfactory cortex hubs and communicated to other brain regions. The underlying oxytocin-induced plasticity promotes the separation of the cortical representations of familiar from other mice. In summary, neuronal encoding of familiar animals is distinct and utilizes the cortical representational space more broadly, promoting storage of complex social relationships.
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Cognición , Odorantes , Oxitocina , Reconocimiento en Psicología , Animales , Oxitocina/farmacología , Oxitocina/metabolismo , Masculino , Ratones , Reconocimiento en Psicología/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Cognición/efectos de los fármacos , Cognición/fisiología , Ratones Endogámicos C57BL , Corteza Olfatoria/fisiología , Conducta Social , Plasticidad Neuronal/efectos de los fármacos , Olfato/fisiología , Olfato/efectos de los fármacos , Memoria/efectos de los fármacos , Memoria/fisiología , Conducta Animal/efectos de los fármacosRESUMEN
Alcohol Use Disorder (AUD) adversely affects the lives of millions of people, but still lacks effective treatment options. Recent advancements in psychedelic research suggest psilocybin to be potentially efficacious for AUD. However, major knowledge gaps remain regarding (1) psilocybin's general mode of action and (2) AUD-specific alterations of responsivity to psilocybin treatment in the brain that are crucial for treatment development. Here, we conducted a randomized, placebo-controlled crossover pharmaco-fMRI study on psilocybin effects using a translational approach with healthy rats and a rat model of alcohol relapse. Psilocybin effects were quantified with resting-state functional connectivity using data-driven whole-brain global brain connectivity, network-based statistics, graph theory, hypothesis-driven Default Mode Network (DMN)-specific connectivity, and entropy analyses. Results demonstrate that psilocybin induced an acute wide-spread decrease in different functional connectivity domains together with a distinct increase of connectivity between serotonergic core regions and cortical areas. We could further provide translational evidence for psilocybin-induced DMN hypoconnectivity reported in humans. Psilocybin showed an AUD-specific blunting of DMN hypoconnectivity, which strongly correlated to the alcohol relapse intensity and was mainly driven by medial prefrontal regions. In conclusion, our results provide translational validity for acute psilocybin-induced neural effects in the rodent brain. Furthermore, alcohol relapse severity was negatively correlated with neural responsivity to psilocybin treatment. Our data suggest that a clinical standard dose of psilocybin may not be sufficient to treat severe AUD cases; a finding that should be considered for future clinical trials.
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Alcoholismo , Alucinógenos , Humanos , Ratas , Animales , Psilocibina/farmacología , Alcoholismo/diagnóstico por imagen , Alcoholismo/tratamiento farmacológico , Red en Modo Predeterminado , Alucinógenos/farmacología , Encéfalo/diagnóstico por imagen , Etanol , Imagen por Resonancia Magnética/métodos , RecurrenciaRESUMEN
OBJECTIVE: Nationwide assessment of structural data and the frequency of use of coercive measures in forensic psychiatric hospitals in Germany. METHODS: Quantitative survey using a postal questionnaire on structural data and on the use of coercive measures in forensic psychiatric hospitals as part of the "ZIPHER" study. RESULTS: About one fourth of all forensic patients are affected by coercive measures, with seclusion (21.2â%) being way more often than mechanical restraint (3.2â%). This ratio contrasts with general psychiatric hospitals, where restraints are more common than seclusions. CONCLUSION: The results of the study reveal nationwide peculiarities in the use of coercive measures in forensic psychiatric hospitals. At the same time, it demonstrated the lack of general structural and process data of forensic hospitals in Germany.
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Psiquiatría Forense , Trastornos Mentales , Coerción , Alemania , Hospitales Psiquiátricos , Humanos , Trastornos Mentales/terapia , Aislamiento de Pacientes , Restricción FísicaRESUMEN
BACKGROUND AND PURPOSE: The benefit of endovascular thrombectomy (EVT) treatment is still unclear in stroke patients presenting with extensive baseline infarct. The use of additional imaging biomarkers could improve clinical outcome prediction and individualized EVT selection in this vulnerable cohort. We hypothesized that cerebral venous outflow (VO) may be associated with functional outcomes in patients with low Alberta Stroke Program Early CT Score (ASPECTS). METHODS: We conducted a retrospective multicenter cohort study of patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). Extensive baseline infarct was defined by an ASPECTS of ≤5 on admission computed tomography (CT). VO profiles were assessed on admission CT angiography using the Cortical Vein Opacification Score (COVES). Favorable VO was defined as COVES ≥3. Multivariable logistic regression was used to determine the association between cerebral VO and good clinical outcomes (90-day modified Rankin Scale score of ≤3). RESULTS: A total of 98 patients met the inclusion criteria. Patients with extensive baseline infarct and favorable VO achieved significantly more often good clinical outcomes compared to patients with unfavorable VO (45.5% vs. 10.5%, P<0.001). Higher COVES were strongly associated with good clinical outcomes (odds ratio, 2.17; 95% confidence interval, 1.15 to 4.57; P=0.024), independent of ASPECTS, National Institutes of Health Stroke Scale, and success of EVT. CONCLUSIONS: Cerebral VO profiles are associated with good clinical outcomes in AIS-LVO patients with extensive baseline infarct. VO profiles could serve as a useful additional imaging biomarker for treatment selection and outcome prediction in low ASPECTS patients.
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Identifying the circuits responsible for cognition and understanding their embedded computations is a challenge for neuroscience. We establish here a hierarchical cross-scale approach, from behavioral modeling and fMRI in task-performing mice to cellular recordings, in order to disentangle local network contributions to olfactory reinforcement learning. At mesoscale, fMRI identifies a functional olfactory-striatal network interacting dynamically with higher-order cortices. While primary olfactory cortices respectively contribute only some value components, the downstream olfactory tubercle of the ventral striatum expresses comprehensively reward prediction, its dynamic updating, and prediction error components. In the tubercle, recordings reveal two underlying neuronal populations with non-redundant reward prediction coding schemes. One population collectively produces stabilized predictions as distributed activity across neurons; in the other, neurons encode value individually and dynamically integrate the recent history of uncertain outcomes. These findings validate a cross-scale approach to mechanistic investigations of higher cognitive functions in rodents.
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Refuerzo en Psicología , Estriado Ventral , Animales , Corteza Cerebral , Imagen por Resonancia Magnética , Ratones , Tubérculo Olfatorio , Recompensa , Estriado Ventral/diagnóstico por imagenRESUMEN
The pleiotropic function of thyroid hormones (TH) is mediated by an organ specific expression of thyroid hormone transporters, deiodinases and TH receptors. In a series of studies we used the model of an experimentally induced hyper- or hypothyroidism in human volunteers to delineate TH action on the brain. A battery of neuropsychological testing paradigms was employed and complemented by structural and functional multimodal neuroimaging. Experimentally induced mild thyrotoxicosis for 6 weeks was associated with changes in brain structure (determined with voxel-based morphometry), resting state functional connectivity, and task-related functional activation in a working memory paradigm. Partial withdrawal of TH replacement in patients without thyroid (subclinical hypothyroidism) likewise lead to changes on multiple functional and structural brain measures. Importantly, the series of studies reviewed here identified the cerebellum as one crucial site of action.
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Encéfalo/anatomía & histología , Encéfalo/fisiología , Conectoma , Hipotiroidismo , Imagen por Resonancia Magnética , Memoria a Corto Plazo/fisiología , Hormonas Tiroideas/fisiología , Tirotoxicosis , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Humanos , Hipotiroidismo/diagnóstico por imagen , Hipotiroidismo/metabolismo , Hipotiroidismo/fisiopatología , Tirotoxicosis/diagnóstico por imagen , Tirotoxicosis/metabolismo , Tirotoxicosis/fisiopatologíaRESUMEN
As ketamine is increasingly used as an effective antidepressant with rapid action, sustaining its short-lived efficacy over a longer period of time using a schedule of repeated injections appears as an option. An open question is whether repeated and single administrations would affect convergent neurocircuits. We used a combination of one of the most robust animal models of depression with high-field neuroimaging to perform a whole-brain delineation of functional mechanisms underlying ketamine's effects. Rats from two genetic strains, depressive-like and resilient, received seven treatments of 10 mg/kg S-ketamine (N = 14 depressive-like, N = 11 resilient) or placebo (N = 12 depressive-like, N = 10 resilient) and underwent resting-state functional magnetic resonance imaging. Using graph theoretical models of brain networks, we compared effects of repeated ketamine with those of single administration from a separate dataset of our previous study. Compared to single treatment, repeated ketamine evoked strain-specific brain network randomization, resembling characteristics of the depressive-like strain and patients. Several affected regions belonged to the auditory, visual, and motor circuitry, hinting at possible cumulative side effects. Finally, when compared to saline, repeated ketamine affected only a few local topological properties and had no effects on global properties. In combination with the lack of clear differences compared to placebo, our findings point toward an inefficacy of ketamine's long-term administration on brain topology, making questionable the postulated effect of repeated administration and being consistent with the recently reported absence of repeated ketamine's antidepressant efficacy in several placebo-controlled studies.
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Ketamina , Animales , Antidepresivos , Encéfalo/diagnóstico por imagen , Humanos , RatasRESUMEN
22q11.2, 15q13.3, and 1q21.1 microdeletions attract considerable interest by conferring high risk for a range of neuropsychiatric disorders, including schizophrenia and autism. A fundamental open question is whether divergent or convergent neural mechanisms mediate this genetic pleiotropic association with the same behavioral phenotypes. We use a combination of rodent microdeletion models with high-field neuroimaging to perform a comparative whole-brain characterization of functional and structural mechanisms linked to high-risk states. Resting-state functional and structural magnetic resonance imaging data were acquired on mice carrying heterozygous microdeletions in 22q11.2 (N = 12), 15q13.3 (N = 11), and 1q21.1 (N = 11) loci. We performed network-based statistic, graph, and morphometric analyses. The three microdeletions did not share significant systems-level features. Instead, morphometric analyses revealed microcephaly in 1q21.1 and macrocephaly in 15q13.3 deletions, whereas cerebellar volume was specifically reduced in 22q11.2 deletion. In function, 22q11.2 deletion mice showed widespread cortical hypoconnectivity, accompanied by opposing hyperconnectivity in dopaminergic pathways, which was confirmed by graph analysis. 1q21.1 exhibited distinct changes in posterior midbrain morphology and function, especially in periaqueductal gray, whereas 15q13.3 demonstrated alterations in auditory/striatal system. The combination of cortical hypoconnectivity and dopaminergic hyperconnectivity and reduced cerebellum in 22q11.2 deletion mirrors key neurodevelopmental features of schizophrenia, whereas changes in midbrain and auditory/striatal morphology and topology in 1q21.1 and 15q13.3 rather indicate focal processes possibly linked to the emergence of abnormal salience perception and hallucinations. In addition to insights into pathophysiological processes in these microdeletions, our results establish the general point that microdeletions might increase risk for overlapping neuropsychiatric phenotypes through separable neural mechanisms.
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Variaciones en el Número de Copia de ADN , Esquizofrenia , Animales , Encéfalo/diagnóstico por imagen , Deleción Cromosómica , Ratones , Fenotipo , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/genéticaRESUMEN
Ketamine acts as a rapid clinical antidepressant at 25 min after injection with effects sustained for 7 days. As dissociative effects emerging acutely after injection are not entirely discernible from therapeutic action, we aimed to dissect the differences between short-term and long-term response to ketamine to elucidate potential imaging biomarkers of ketamine's antidepressant effect. We used a genetical model of depression, in which we bred depressed negative cognitive state (NC) and non-depressed positive cognitive state (PC) rat strains. Four parallel rat groups underwent stress-escape testing and a week later received either S-ketamine (12 NC, 13 PC) or saline (12 NC, 12 PC). We acquired resting-state functional magnetic resonance imaging time series before injection and at 30 min and 48 h after injection. Graph analysis was used to calculate brain network properties. We identified ketamine's distinct action over time in a qualitative manner. The rapid response entailed robust and strain-independent topological modifications in cognitive, sensory, emotion, and reward-related circuitry, including regions that exhibited correlation of connectivity metrics with depressive behavior, and which could explain ketamine's dissociative and antidepressant properties. At 48 h ketamine had mainly strain-specific action normalizing habenula, midline thalamus, and hippocampal connectivity measures in depressed rats. As these nodes mediate cognitive flexibility impaired in depression, action within this circuitry presumably reflects ketamine's procognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. These empirically defined circuits explain ketamine's distinct action over time and might serve as translational imaging correlates of antidepressant response in preclinical testing.
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Antidepresivos/farmacología , Cerebro/efectos de los fármacos , Conectoma , Depresión/tratamiento farmacológico , Ketamina/farmacología , Red Nerviosa/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Cerebro/diagnóstico por imagen , Cerebro/fisiopatología , Modelos Animales de Enfermedad , Habénula/diagnóstico por imagen , Habénula/efectos de los fármacos , Habénula/fisiopatología , Hipocampo/diagnóstico por imagen , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología , Ratas , Ratas Sprague-Dawley , Tálamo/diagnóstico por imagen , Tálamo/efectos de los fármacos , Tálamo/fisiopatologíaRESUMEN
RATIONALE: Evidence indicates that ketamine's rapid antidepressant efficacy likely results from its antagonism of NR2B-subunit-containing NMDA receptors (NMDAR). Since ketamine equally blocks NR2A- and NR2B-containing NMDAR, and has affinity to other receptors, NR2B-selective drugs might have improved therapeutic efficiency and side effect profile. OBJECTIVES: We aimed to compare the effects of (S)-ketamine and two different types of NR2B-selective antagonists on functional brain networks in rats, in order to find common circuits, where their effects intersect, and that might explain their antidepressant action. METHODS: The experimental design comprised four parallel groups of rats (N = 37), each receiving (S)-Ketamine, CP-101,606, Ro 25-6981 or saline. After compound injection, we acquired resting-state functional magnetic resonance imaging time series. We used graph theoretical approach to calculate brain network properties. RESULTS: Ketamine and CP-101,606 diminished the global clustering coefficient and small-worldness index. At the nodal level, all compounds induced increased connectivity of the regions mediating reward and cognitive aspects of emotional processing, such as ventromedial prefrontal cortex, septal nuclei, and nucleus accumbens. The dorsal hippocampus and regions involved in sensory processing and aversion, such as superior and inferior colliculi, exhibited an opposite effect. CONCLUSIONS: The effects common to ketamine and NR2B-selective compounds were localized to the same brain regions as those reported in depression, but in the opposite direction. The upregulation of the reward circuitry might partially underlie the antidepressant and anti-anhedonic effects of the antagonists and could potentially serve as a translational imaging phenotype for testing putative antidepressants, especially those targeting the NR2B receptor subtype.
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Antagonistas de Aminoácidos Excitadores/farmacología , Red Nerviosa/fisiología , Corteza Prefrontal/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/fisiología , Recompensa , Animales , Antidepresivos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Ketamina/farmacología , Masculino , Red Nerviosa/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Fenoles/farmacología , Piperidinas/farmacología , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Hyperconnectivity of the default-mode network (DMN) is one of the most widely replicated neuroimaging findings in major depressive disorder (MDD). Further, there is growing evidence for a central role of the lateral habenula (LHb) in the pathophysiology of MDD. There is preliminary neuroimaging evidence linking LHb and the DMN, but no causal relationship has been shown to date. We combined optogenetics and functional magnetic resonance imaging (fMRI), to establish a causal relationship, using an animal model of treatment-resistant depression, namely Negative Cognitive State rats. First, an inhibitory light-sensitive ion channel was introduced into the LHb by viral transduction. Subsequently, laser stimulation was performed during fMRI acquisition on a 9.4 Tesla animal scanner. Neural activity and connectivity were assessed, before, during and after laser stimulation. We observed a connectivity decrease in the DMN following laser-induced LHb perturbation. Our data indicate a causal link between LHb downregulation and reduction in DMN connectivity. These findings may advance our mechanistic understanding of LHb inhibition, which had previously been identified as a promising therapeutic principle, especially for treatment-resistant depression.
Asunto(s)
Encéfalo/fisiopatología , Trastorno Depresivo Resistente al Tratamiento/fisiopatología , Habénula/fisiopatología , Animales , Mapeo Encefálico , Modelos Animales de Enfermedad , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/fisiopatología , Optogenética , RatasRESUMEN
BACKGROUND: To explore the domain-general risk factor of early-life social stress in mental illness, rearing rodents in persistent postweaning social isolation has been established as a widely used animal model with translational relevance for neurodevelopmental psychiatric disorders such as schizophrenia. Although changes in resting-state brain connectivity are a transdiagnostic key finding in neurodevelopmental diseases, a characterization of imaging correlates elicited by early-life social stress is lacking. METHODS: We performed resting-state functional magnetic resonance imaging of postweaning social isolation rats (N = 23) 9 weeks after isolation. Addressing well-established transdiagnostic connectivity changes of psychiatric disorders, we focused on altered frontal and posterior connectivity using a seed-based approach. Then, we examined changes in regional network architecture and global topology using graph theoretical analysis. RESULTS: Seed-based analyses demonstrated reduced functional connectivity in frontal brain regions and increased functional connectivity in posterior brain regions of postweaning social isolation rats. Graph analyses revealed a shift of the regional architecture, characterized by loss of dominance of frontal regions and emergence of nonfrontal regions, correlating to our behavioral results, and a reduced modularity in isolation-reared rats. CONCLUSIONS: Our result of functional connectivity alterations in the frontal brain supports previous investigations postulating social neural circuits, including prefrontal brain regions, as key pathways for risk for mental disorders arising through social stressors. We extend this knowledge by demonstrating more widespread changes of brain network organization elicited by early-life social stress, namely a shift of hubness and dysmodularity. Our results highly resemble core alterations in neurodevelopmental psychiatric disorders such as schizophrenia, autism, and attention-deficit/hyperactivity disorder in humans.