RESUMEN
As a critical node connecting the forebrain with the midbrain, the lateral habenula (LHb) processes negative feedback in response to aversive events and plays an essential role in value-based decision-making. Compulsive drug use, a hallmark of substance use disorder, is attributed to maladaptive decision-making regarding aversive drug-use-related events and has been associated with dysregulation of various frontal-midbrain circuits. To understand the contributions of frontal-habenula-midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration (SA) in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, functional MRI data were collected at pretraining baseline, after 20 d of long-access SA phase, and after 5 d of concomitant footshock coupled with SA (punishment phase). Individual differences in response to punishment were quantified by a "compulsivity index (CI)," defined as drug infusions at the end of punishment phase, normalized by those at the end of SA phase. Functional connectivity of LHb with the frontal cortices and substantia nigra (SN) after the punishment phase was positively correlated with the CI in rats that maintained drug SA despite receiving increasing-intensity footshock. In contrast, functional connectivity of the same circuits was negatively correlated with CI in rats that significantly reduced SA. These findings suggest that individual differences in compulsive drug-taking are reflected by alterations within frontal-LHb-SN circuits after experiencing the negative consequences from SA, suggesting these circuits may serve as unique biomarkers and potential therapeutic targets for individualized treatment of addiction.
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Habénula , Metanfetamina , Trastornos Relacionados con Sustancias , Humanos , Ratas , Animales , Habénula/fisiología , Estudios Longitudinales , Conducta Compulsiva , Lóbulo Frontal/diagnóstico por imagenRESUMEN
BACKGROUND: Alcohol and nicotine interact with the nicotinic acetylcholine receptor system to alter reward-related responses, thereby contributing to the co-use and misuse of these drugs. A missense polymorphism rs16969968 (G>A) in the CHRNA5 gene has shown a strong association with nicotine-related phenotypes. However, less is known about the impact of this variant on alcohol-related phenotypes. METHODS: We assessed the main and interactive effect of smoking and rs16969968 polymorphism on alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT), Timeline Follow Back (TLFB), and Lifetime Drinking History (LDH) in 980 healthy adults without alcohol use disorder. We further examined the effect of the rs16969968 polymorphism on acute alcohol consumption using a free-access intravenous alcohol self-administration (IV-ASA) human laboratory paradigm in a subset of 153 non-smoking participants. Subjective alcohol responses, alcohol sensitivity, and expectancy measures were compared between genotype groups (GG; AA/AG). RESULTS: We observed a significant association of smoking with AUDIT, TLFB, and LDH measures across genotype groups, with smokers showing higher scores compared to non-smokers. Additionally, we found an association between genotype and TLFB-total drinks in the IV-ASA subset, with the GG group showing higher scores than AA/AG group. Relatedly, the alcohol negative expectancy score was significantly lower in the GG group than the AA/AG group. CONCLUSIONS: Our findings underscore the association of smoking with alcohol measures. We found preliminary evidence for the protective effect of the functional CHRNA5 polymorphism on alcohol consumption and its association with increased negative alcohol expectancies, which highlights the substantial heterogeneity in alcohol responses.
RESUMEN
Striatal loci are connected to both the ipsilateral and contralateral frontal cortex. Normative quantitation of the dissimilarity between striatal loci's hemispheric connection profiles and its spatial variance across the striatum, and assessment of how interindividual differences relate to function, stands to further the understanding of the role of corticostriatal circuits in lateralized functions and the role of abnormal corticostriatal laterality in neurodevelopmental and other neuropsychiatric disorders. A resting-state functional connectivity fingerprinting approach (n = 261) identified "laterality hotspots"-loci whose profiles of connectivity with ipsilateral and contralateral frontal cortex were disproportionately dissimilar-in the right rostral ventral putamen, left rostral central caudate, and bilateral caudal ventral caudate. Findings were replicated in an independent sample and were robust to both preprocessing choices and the choice of cortical atlas used for parcellation definitions. Across subjects, greater rightward connectional laterality at the right ventral putamen hotspot and greater leftward connectional laterality at the left rostral caudate hotspot were associated with higher performance on tasks engaging lateralized functions (i.e., response inhibition and language, respectively). In sum, we find robust and reproducible evidence for striatal loci with disproportionately lateralized connectivity profiles where interindividual differences in laterality magnitude are associated with behavioral capacities on lateralized functions.
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Cuerpo Estriado , Imagen por Resonancia Magnética , Mapeo Encefálico , Cuerpo Estriado/fisiología , Lateralidad Funcional/fisiología , Humanos , Vías Nerviosas/fisiología , Putamen/fisiologíaRESUMEN
Cognitive aging varies tremendously across individuals and is often accompanied by regionally specific reductions in gray matter (GM) volume, even in the absence of disease. Rhesus monkeys provide a primate model unconfounded by advanced neurodegenerative disease, and the current study used a recognition memory test (delayed non-matching to sample; DNMS) in conjunction with structural imaging and voxel-based morphometry (VBM) to characterize age-related differences in GM volume and brain-behavior relationships. Consistent with expectations from a long history of neuropsychological research, DNMS performance in young animals prominently correlated with the volume of multiple structures in the medial temporal lobe memory system. Less anticipated correlations were also observed in the cingulate and cerebellum. In aged monkeys, significant volumetric correlations with DNMS performance were largely restricted to the prefrontal cortex and striatum. Importantly, interaction effects in an omnibus analysis directly confirmed that the associations between volume and task performance in the MTL and prefrontal cortex are age-dependent. These results demonstrate that the regional distribution of GM volumes coupled with DNMS performance changes across the lifespan, consistent with the perspective that the aged primate brain retains a substantial capacity for structural reorganization.
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Sustancia Gris , Enfermedades Neurodegenerativas , Envejecimiento , Animales , Sustancia Gris/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Reconocimiento en PsicologíaRESUMEN
Substance use disorders (SUDs) impose severe negative impacts upon individuals, their families, and society. Clinical studies demonstrate that some chronic stimulant users are able to curtail their drug use when faced with adverse consequences while others continue to compulsively use drugs. The mechanisms underlying this dichotomy are poorly understood, which hampers the development of effective individualized treatments of a disorder that currently has no Food and Drug Administration-approved pharmacological treatments. In the present study, using a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, we found that SA behavior correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal "go" circuit and a decreased prelimbic cortex-ventrolateral striatal "stop" circuit. Critically, this correlation was seen only in rats who continued to self-administer at a relatively high rate despite receiving foot shocks of increasing intensity. While the stop circuit functional connectivity became negative after repeated SA in all rats, "shock-resistant" rats showed strengthening of this negative connectivity after shock exposure. In contrast, "shock-sensitive" rats showed a return toward their baseline levels after shock exposure. These results may help guide novel noninvasive brain stimulation therapies aimed at restoring the physiological balance between stop and go circuits in SUDs.
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Conducta Compulsiva/fisiopatología , Castigo/psicología , Trastornos Relacionados con Sustancias/psicología , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Conectoma/métodos , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Electrochoque/métodos , Masculino , Metanfetamina/farmacología , Corteza Prefrontal/fisiopatología , Ratas , Ratas Sprague-Dawley , Autoadministración , Trastornos Relacionados con Sustancias/fisiopatologíaRESUMEN
Longitudinal non-human primate neuroimaging has the potential to greatly enhance our understanding of primate brain structure and function. Here we describe its specific strengths, compared to both cross-sectional non-human primate neuroimaging and longitudinal human neuroimaging, but also its associated challenges. We elaborate on factors guiding the use of different analytical tools, subject-specific versus age-specific templates for analyses, and issues related to statistical power.
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Envejecimiento , Desarrollo Humano , Neuroimagen , Primates , Animales , Estudios Transversales , Imagen de Difusión Tensora/métodos , Imagen de Difusión Tensora/normas , Neuroimagen Funcional/métodos , Neuroimagen Funcional/normas , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Neuroimagen/métodos , Neuroimagen/normasRESUMEN
Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.
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Corteza Cerebelosa/patología , Trastornos Relacionados con Sustancias/diagnóstico por imagen , Adulto , Alcoholismo/diagnóstico por imagen , Conducta Adictiva/diagnóstico por imagen , Encéfalo/patología , Grosor de la Corteza Cerebral , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Núcleo Accumbens/patología , Tabaquismo/diagnóstico por imagen , Adulto JovenRESUMEN
Although 60% of the US population have tried smoking cigarettes, only 16% smoke regularly. Identifying this susceptible subset of the population before the onset of nicotine dependence may encourage targeted early interventions to prevent regular smoking and/or minimize severity. While prospective neuroimaging in human populations can be challenging, preclinical neuroimaging models before chronic nicotine administration can help to develop translational biomarkers of disease risk. Chronic, intermittent nicotine (0, 1.2, or 4.8 mg/kg/d; N = 10-11/group) was administered to male Sprague Dawley rats for 14 d; dependence severity was quantified using precipitated withdrawal behaviors collected before, during, and following forced nicotine abstinence. Resting-state fMRI functional connectivity (FC) before drug administration was subjected to a graph theory analytical framework to form a predictive model of subsequent individual differences in nicotine dependence. Whole-brain modularity analysis identified five modules in the rat brain. A metric of intermodule connectivity, participation coefficient, of an identified insular-frontal cortical module predicted subsequent dependence severity, independent of nicotine dose. To better spatially isolate this effect, this module was subjected to a secondary exploratory modularity analysis, which segregated it into three submodules (frontal-motor, insular, and sensory). Higher FC among these three submodules and three of the five originally identified modules (striatal, frontal-executive, and sensory association) also predicted dependence severity. These data suggest that predispositional, intrinsic differences in circuit strength between insular-frontal-based brain networks before drug exposure may identify those at highest risk for the development of nicotine dependence.SIGNIFICANCE STATEMENT Developing biomarkers of individuals at high risk for addiction before the onset of this brain-based disease is essential for prevention, early intervention, and/or subsequent treatment decisions. Using a rodent model of nicotine dependence and a novel data-driven, network-based analysis of resting-state fMRI data collected before drug exposure, functional connections centered on an intrinsic insular-frontal module predicted the severity of nicotine dependence after drug exposure. The predictive capacity of baseline network measures was specific to inter-regional but not within-region connectivity. While insular and frontal regions have consistently been implicated in nicotine dependence, this is the first study to reveal that innate, individual differences in their circuit strength have the predictive capacity to identify those at greatest risk for and resilience to drug dependence.
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Corteza Cerebral/diagnóstico por imagen , Lóbulo Frontal/diagnóstico por imagen , Red Nerviosa/diagnóstico por imagen , Nicotina/administración & dosificación , Síndrome de Abstinencia a Sustancias/diagnóstico por imagen , Tabaquismo/diagnóstico por imagen , Animales , Corteza Cerebral/efectos de los fármacos , Lóbulo Frontal/efectos de los fármacos , Neuroimagen Funcional , Pruebas Genéticas , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/efectos de los fármacos , Nicotina/efectos adversos , Ratas , Ratas Sprague-Dawley , Índice de Severidad de la EnfermedadRESUMEN
Spontaneous ongoing neuronal activity is a prominent feature of the mammalian brain. Temporal and spatial patterns of such ongoing activity have been exploited to examine large-scale brain network organization and function. However, the neurophysiological basis of this spontaneous brain activity as detected by resting-state functional Magnetic Resonance Imaging (fMRI) remains poorly understood. To this end, multi-site local field potentials (LFP) and blood oxygenation level-dependent (BOLD) fMRI were simultaneously recorded in the rat striatum along with local pharmacological manipulation of striatal activity. Results demonstrate that delta (δ) band LFP power negatively, while beta (ß) and gamma (γ) band LFPs positively correlated with BOLD fluctuation. Furthermore, there was strong cross-frequency phase-amplitude coupling (PAC), with the phase of δ LFPs significantly modulating the amplitude of the high frequency signal. Enhancing dopaminergic neuronal activity significantly reduced ventral striatal functional connectivity, δ LFP-BOLD correlation, and the PAC effect. These data suggest that different frequency bands of the LFP contribute distinctively to BOLD spontaneous fluctuation and that PAC is the organizing mechanism through which low frequency LFPs orchestrate neural activity that underlies resting state functional connectivity.
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Ritmo Delta/fisiología , Imagen por Resonancia Magnética/métodos , Red Nerviosa/diagnóstico por imagen , Consumo de Oxígeno/fisiología , Descanso/fisiología , Estriado Ventral/diagnóstico por imagen , Animales , Masculino , Red Nerviosa/metabolismo , Ratas , Ratas Sprague-Dawley , Estriado Ventral/metabolismoRESUMEN
While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.
Asunto(s)
Encéfalo/diagnóstico por imagen , Neuroimagen , Trastornos Relacionados con Sustancias/diagnóstico por imagen , Adolescente , Adulto , Cannabis/efectos adversos , Cocaína/efectos adversos , Etanol/efectos adversos , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Metanfetamina/efectos adversos , Nicotina/efectos adversos , Adulto JovenRESUMEN
To date, fractionation of the nicotine addiction phenotype has been limited to that based primarily on characteristics of cigarette use, although it is widely appreciated that a variety of individual factors are associated with tobacco use disorder. Identifying subtypes of tobacco use disorder based on such factors may lead to better understanding of potential treatment targets, individualize treatments and improve outcomes. In this preliminary study, to identify potential subgroups, we applied hierarchical clustering to a broad range of assessments measuring personality, IQ and psychiatric symptoms, as well as various environmental and experiential characteristics from 102 otherwise healthy cigarette smokers. The identified subgroups were further compared on various resting-state fMRI measures from a subset (N = 65) of individuals who also underwent resting-state fMRI scanning. The clustering dendrogram indicated that smokers can be divided into three subgroups. Each subgroup had unique clinical assessment characteristics. The division yielded imaging differences between subgroups in the supplementary motor area/middle cingulate cortex and the cuneus. Regression analyses showed that amplitude of low frequency fluctuations in the supplementary motor area/middle cingulate cortex differed between groups and were negatively correlated with the Toronto Alexithymia Scale subscale Difficulty Describing Feelings.
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Síntomas Afectivos/diagnóstico por imagen , Giro del Cíngulo/diagnóstico por imagen , Corteza Motora/diagnóstico por imagen , Lóbulo Occipital/diagnóstico por imagen , Tabaquismo/diagnóstico por imagen , Adulto , Experiencias Adversas de la Infancia/psicología , Síntomas Afectivos/psicología , Ansiedad/psicología , Fumar Cigarrillos/psicología , Análisis por Conglomerados , Depresión/psicología , Femenino , Neuroimagen Funcional , Giro del Cíngulo/fisiopatología , Humanos , Pruebas de Inteligencia , Imagen por Resonancia Magnética , Masculino , Corteza Motora/fisiopatología , Lóbulo Occipital/fisiopatología , Distrés Psicológico , Temperamento , Tabaquismo/clasificación , Tabaquismo/fisiopatología , Tabaquismo/psicología , Aprendizaje Automático no Supervisado , Adulto JovenRESUMEN
Changes in the functional connectivity (FC) of large-scale brain networks are a prominent feature of brain aging, but defining their relationship to variability along the continuum of normal and pathological cognitive outcomes has proved challenging. Here we took advantage of a well-characterized rat model that displays substantial individual differences in hippocampal memory during aging, uncontaminated by slowly progressive, spontaneous neurodegenerative disease. By this approach, we aimed to interrogate the underlying neural network substrates that mediate aging as a uniquely permissive condition and the primary risk for neurodegeneration. Using resting state (rs) blood oxygenation level-dependent fMRI and a restrosplenial/posterior cingulate cortex seed, aged rats demonstrated a large-scale network that had a spatial distribution similar to the default mode network (DMN) in humans, consistent with earlier findings in younger animals. Between-group whole brain contrasts revealed that aged subjects with documented deficits in memory (aged impaired) displayed widespread reductions in cortical FC, prominently including many areas outside the DMN, relative to both young adults (Y) and aged rats with preserved memory (aged unimpaired, AU). Whereas functional connectivity was relatively preserved in AU rats, they exhibited a qualitatively distinct network signature, comprising the loss of an anticorrelated network observed in Y adults. Together the findings demonstrate that changes in rs-FC are specifically coupled to variability in the cognitive outcome of aging, and that successful neurocognitive aging is associated with adaptive remodeling, not simply the persistence of youthful network dynamics.
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Envejecimiento/fisiología , Envejecimiento Cognitivo/fisiología , Hipocampo/fisiología , Degeneración Nerviosa/fisiopatología , Animales , Sangre , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/fisiopatología , Hipocampo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Memoria/fisiología , Degeneración Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología , RatasRESUMEN
The default mode network (DMN) has been suggested to support a variety of self-referential functions in humans and has been fractionated into subsystems based on distinct responses to cognitive tasks and functional connectivity architecture. Such subsystems are thought to reflect functional hierarchy and segregation within the network. Because preclinical models can inform translational studies of neuropsychiatric disorders, partitioning of the DMN in nonhuman species, which has previously not been reported, may inform both physiology and pathophysiology of the human DMN. In this study, we sought to identify constituents of the rat DMN using resting-state functional MRI (rs-fMRI) and diffusion tensor imaging. After identifying DMN using a group-level independent-component analysis on the rs-fMRI data, modularity analyses fractionated the DMN into an anterior and a posterior subsystem, which were further segregated into five modules. Diffusion tensor imaging tractography demonstrates a close relationship between fiber density and the functional connectivity between DMN regions, and provides anatomical evidence to support the detected DMN subsystems. Finally, distinct modulation was seen within and between these DMN subcomponents using a neurocognitive aging model. Taken together, these results suggest that, like the human DMN, the rat DMN can be partitioned into several subcomponents that may support distinct functions. These data encourage further investigation into the neurobiological mechanisms of DMN processing in preclinical models of both normal and disease states.
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Encéfalo/fisiología , Red Nerviosa/fisiología , Vías Nerviosas/fisiología , Descanso/fisiología , Animales , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Imagen de Difusión Tensora/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Modelos Animales , Red Nerviosa/diagnóstico por imagen , Vías Nerviosas/diagnóstico por imagen , Ratas Sprague-DawleyRESUMEN
While chronic cocaine use is associated with abnormalities in both brain structure and function within and interactions between regions, previous studies have been limited to interrogating structure and function independently, and the detected neural differences have not been applied to independent samples to assess the clinical relevance of results. We investigated consequences of structural differences on resting-state functional connectivity in cocaine addiction and tested whether resting-state functional connectivity of the identified circuits predict relapse in an independent cohort. Subjects included 64 non-treatment-seeking cocaine users (NTSCUs) and 67 healthy control subjects and an independent treatment-completed cohort (n = 45) of cocaine-dependent individuals scanned at the end of a 30-day residential treatment programme. Differences in cortical thickness and related resting-state functional connectivity between NTSCUs and healthy control subjects were identified. Survival analysis, applying cortical thickness of the identified regions, resting-state functional connectivity of the identified circuits and clinical characteristics to the treatment cohort, was used to predict relapse. Lower cortical thickness in bilateral insula and higher thickness in bilateral temporal pole were found in NTSCUs versus healthy control subjects. Whole brain resting-state functional connectivity analyses with these four different anatomical regions as seeds revealed eight weaker circuits including within the salience network (insula seeds) and between temporal pole and elements of the default mode network in NTSCUs. Applying these circuits and clinical characteristics to the independent cocaine-dependent treatment cohort, functional connectivity between right temporal pole and medial prefrontal cortex, combined with years of education, predicted relapse status at 150 days with 88% accuracy. Deficits in the salience network suggest an impaired ability to process physiologically salient events, while abnormalities in a temporal pole-medial prefrontal cortex circuit might speak to the social-emotional functional alterations in cocaine addiction. The involvement of the temporal pole-medial prefrontal cortex circuit in a model highly predictive of relapse highlights the importance of social-emotional functions in cocaine dependence, and provides a potential underlying neural target for therapeutic interventions, and for identifying those at high risk of relapse.
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Corteza Cerebral/fisiopatología , Trastornos Relacionados con Cocaína/fisiopatología , Corteza Prefrontal/fisiopatología , Lóbulo Temporal/fisiopatología , Adulto , Estudios de Casos y Controles , Corteza Cerebral/patología , Trastornos Relacionados con Cocaína/patología , Estudios de Cohortes , Femenino , Neuroimagen Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Corteza Prefrontal/patología , Recurrencia , Lóbulo Temporal/patología , Resultado del TratamientoRESUMEN
BACKGROUND: The glymphatic pathway transports cerebrospinal fluid through the brain, thereby facilitating waste removal. A unique aspect of this pathway is that its function depends on the state of consciousness of the brain and is associated with norepinephrine activity. A current view is that all anesthetics will increase glymphatic transport by inducing unconsciousness. This view implies that the effect of anesthetics on glymphatic transport should be independent of their mechanism of action, as long as they induce unconsciousness. We tested this hypothesis by comparing the supplementary effect of dexmedetomidine, which lowers norepinephrine, with isoflurane only, which does not. METHODS: Female rats were anesthetized with either isoflurane (N = 8) or dexmedetomidine plus low-dose isoflurane (N = 8). Physiologic parameters were recorded continuously. Glymphatic transport was quantified by contrast-enhanced magnetic resonance imaging. Cerebrospinal fluid and gray and white matter volumes were quantified from T1 maps, and blood vessel diameters were extracted from time-of-flight magnetic resonance angiograms. Electroencephalograms were recorded in separate groups of rats. RESULTS: Glymphatic transport was enhanced by 32% in rats anesthetized with dexmedetomidine plus low-dose isoflurane when compared with isoflurane. In the hippocampus, glymphatic clearance was sixfold more efficient during dexmedetomidine plus low-dose isoflurane anesthesia when compared with isoflurane. The respiratory and blood gas status was comparable in rats anesthetized with the two different anesthesia regimens. In the dexmedetomidine plus low-dose isoflurane rats, spindle oscillations (9 to 15 Hz) could be observed but not in isoflurane anesthetized rats. CONCLUSIONS: We propose that anesthetics affect the glymphatic pathway transport not simply by inducing unconsciousness but also by additional mechanisms, one of which is the repression of norepinephrine release.
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Dexmedetomidina/administración & dosificación , Gadolinio DTPA/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Isoflurano/administración & dosificación , Transducción de Señal/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Anestésicos por Inhalación/administración & dosificación , Animales , Transporte Biológico/efectos de los fármacos , Transporte Biológico/fisiología , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Hipocampo/diagnóstico por imagen , Hipnóticos y Sedantes/administración & dosificación , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Imagen por Resonancia Magnética/métodos , Ratas , Ratas Endogámicas F344 , Transducción de Señal/fisiologíaRESUMEN
Resting-state magnetic resonance imaging (rsMRI) is thought to reflect ongoing spontaneous brain activity. However, the precise neurophysiological basis of rsMRI signal remains elusive. Converging evidence supports the notion that local field potential (LFP) signal in the high-frequency range correlates with fMRI response evoked by a task (e.g., visual stimulation). It remains uncertain whether this relationship extends to rsMRI. In this study, we systematically modulated LFP signal in the whisker barrel cortex (WBC) by unilateral deflection of rat whiskers. Results show that functional connectivity between bilateral WBC was significantly modulated at the 2 Hz, but not at the 4 or 6 Hz, stimulus condition. Electrophysiologically, only in the low-frequency range (<5 Hz) was the LFP power synchrony in bilateral WBC significantly modulated at 2 Hz, but not at 4- or 6-Hz whisker stimulation, thus distinguishing these 2 experimental conditions, and paralleling the findings in rsMRI. LFP power synchrony in other frequency ranges was modulated in a way that was neither unique to the specific stimulus conditions nor parallel to the fMRI results. Our results support the hypothesis that emphasizes the role of low-frequency LFP signal underlying rsMRI.
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Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/fisiología , Potenciales Evocados Somatosensoriales/fisiología , Vibrisas/inervación , Animales , Biofisica , Dexmedetomidina/farmacología , Electroencefalografía , Potenciales Evocados Somatosensoriales/efectos de los fármacos , Análisis de Fourier , Lateralidad Funcional/efectos de los fármacos , Lateralidad Funcional/fisiología , Hipnóticos y Sedantes/farmacología , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Oxígeno/sangre , Estimulación Física , Ratas , Ratas Sprague-DawleyRESUMEN
The posterior hippocampus (pHp) plays a major role in the processing and storage of drug-related cues and is linked to striatal-limbic brain circuits involved with craving and drug salience. We have recently reported that increased basal regional cerebral blood flow (rCBF) in a pHp loci, as measured by pseudo-continuous arterial spin labeling magnetic resonance imaging, predicted days to cocaine relapse following residential treatment. In this secondary analysis, we explored whether rCBF in this same pHp region would successfully predict 30-day point prevalence abstinence 60 days following residential treatment in an independent group of previously studied participants with cocaine dependence. rCBF was assessed with single photon emission computerized tomography during a saline infusion in 21 cocaine dependence and 22 healthy control participants. pHp rCBF was significantly higher in those endorsing substance use (n = 10) relative to both abstinent (n = 11) (p < 0.001) and control (p < 0.05) participants. There were no significant differences in measured demographic or clinical variables between the actively using and non-using participants. This replicative finding suggests that heightened pHp activation is a significant predictor of substance use in cocaine-dependent individuals, possibly reflecting a neural susceptibility to continued drug cues.
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Circulación Cerebrovascular/fisiología , Trastornos Relacionados con Cocaína/fisiopatología , Hipocampo/irrigación sanguínea , Hipocampo/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único/métodos , Adulto , Femenino , Humanos , Masculino , Recurrencia , Reproducibilidad de los ResultadosRESUMEN
Cocaine addiction is characterized by notoriously high relapse rates following treatment. Recent efforts to address poor treatment outcomes have turned to potential neural markers of relapse risk. Accordingly, the present study examined resting state functional connectivity (rsFC) within and between three large-scale cortical networks: the default mode network (DMN), salience network (SN) and executive control network (ECN). All three have been implicated in relapse-related phenomena including craving, withdrawal and executive control deficits. Forty-five cocaine-dependent individuals and 22 healthy controls completed 6-min resting fMRI scans, The Wisconsin Card Sorting Task, Continuous Performance Test and Cocaine Craving Questionnaire. Cocaine-dependent individuals completed all measures in the final week of a residential treatment episode. Ten control and 9 abstinent cocaine-dependent individuals returned for 3-6 month follow-up scan visits. A group-level independent component analysis was employed to generate ECN, DMN and SN components. For individuals abstinent up to day 30 post-treatment (n = 21), we found enhanced pre-discharge rsFC between the left ECN and both the right ECN and SN as well as between the right ECN and left ECN. Left ECN rsFC effects remained elevated 3-6 months later among abstinent cocaine-dependent individuals. Relapse was related to fewer years of education and more years smoking but no other demographic, clinical, treatment and neurocognitive characteristics. Findings suggest that interhemispheric ECN and ECN-SN connectivity strength may protect against relapse to cocaine use following treatment. These patterns of enhanced interhemispheric network connectivity may reflect a greater capacity to engage executive control processes when faced with opportunities to use cocaine post-treatment.
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Encéfalo/fisiopatología , Trastornos Relacionados con Cocaína/fisiopatología , Función Ejecutiva/efectos de los fármacos , Adulto , Mapeo Encefálico/métodos , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , RecurrenciaRESUMEN
Distress tolerance (DT), defined as the ability to persist in goal directed behavior while experiencing affective distress, is implicated in the development and maintenance of substance use disorders. While theory and evidence indicate that cortico-limbic neural dysfunction may account for deficits in goal directed behavior while experiencing distress, the neurobiological mechanisms of DT have yet to be examined. We modified a computerized DT task for use in functional magnetic resonance imaging (fMRI), the Paced Auditory Serial Addition Task (PASAT-M), and examined the neural correlates and functional connectivity of DT among a cohort of substance users (n = 21; regular cocaine and nicotine users) and healthy controls (n = 25). In response to distress during the PASAT-M, we found greater activation in a priori cortico-limbic network ROIs, namely the right insula, anterior cingulate cortex (ACC), bilateral medial frontal gyrus (MFG), right inferior frontal gyrus (IFG) and right ventromedial prefrontal cortex (vmPFC) significantly predicted higher DT among substance users, but not healthy controls. In addition, greater task-specific functional connectivity during distress between the right MFG and bilateral vmPFC/sgACC was associated with higher DT among substance users, but not healthy controls. The observed positive relationship between DT and neural activation in cortico-limbic structures, as well as functional connectivity between the rMFG and vmPFC/sgACC, is in line with theory and research suggesting the importance of these structures for persisting in goal directed behavior while experiencing affective distress.
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Trastornos Relacionados con Cocaína/diagnóstico por imagen , Giro del Cíngulo/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagen , Estrés Psicológico/diagnóstico por imagen , Tabaquismo/diagnóstico por imagen , Adulto , Estudios de Casos y Controles , Trastornos Relacionados con Cocaína/psicología , Estudios de Cohortes , Femenino , Neuroimagen Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas , Estrés Psicológico/psicología , Trastornos Relacionados con Sustancias/diagnóstico por imagen , Trastornos Relacionados con Sustancias/psicología , Tabaquismo/psicologíaRESUMEN
Cocaine dependence is a complex neuropsychiatric disorder manifested as dysregulation of multiple behavioral, emotional, and cognitive constructs. Neuroimaging studies have begun to identify specific neurobiological circuit impairments in cocaine-dependent (CD) individuals that may underlie these symptoms. However, whether, where, and how the interactions within and between these circuits are disrupted remain largely unknown. We used resting-state fMRI and modularity network analysis to identify brain modules of a priori interest (default-mode network [DMN], salience network [SN], executive control network [ECN], medial temporal lobe [MTL], and striatum) in 47 CD and 47 matched healthy control (HC) participants and explored alterations within and between these brain modules as a function of addiction. At the module level, intermodule connectivity decreased between DMN and SN in CD. At the nodal level, several regions showed decreased connections with multiple modules in CD: the rostral anterior cingulate connection strength was reduced with SN and MTL; the posterior cingulate had reduced connections with ECN; and the bilateral insula demonstrated decreased connections with DMN. Furthermore, alexithymia, a personality trait previously associated with addiction, correlated negatively with intramodule connectivity within SN only in cocaine users. Our results indicate that cocaine addiction is associated with disrupted interactions among DMN, MTL, and SN, which have been implicated, respectively, in self-referential functions, emotion and memory, and coordinating between internal and external stimuli, providing novel and important insights into the neurobiological mechanisms of cocaine addiction.