Model‐free functional connectivity and impulsivity correlates of alcohol dependence: a resting‐state study

Zhu, Xi; Cortes, Carlos R.; Mathur, Karan; Tomasi, Dardo; Momenan, Reza

doi:10.1111/adb.12272

Cited by 126 publications

(139 citation statements)

References 31 publications

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“…Normalized protein expression data were analyzed with a one-tailed t test, and standard linear regression was used to analyze protein expression levels with optical density values and average daily alcohol intake. The specificity of this antibody for Western blots has been confirmed in GluA1 knock-out mice (Zamanillo et al, 1999) and characterized using human, macaque, and rodent tissue from frontal cortex (Tucholski et al, 2014).…”

Section: Methodsmentioning

confidence: 88%

Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques

Nimitvilai¹,

Uys

Woodward

et al. 2017

J. Neurosci.

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Cognitive impairments, uncontrolled drinking, and neuropathological cortical changes characterize alcohol use disorder. Dysfunction of the orbitofrontal cortex (OFC), a critical cortical subregion that controls learning, decision-making, and prediction of reward outcomes, contributes to executive cognitive function deficits in alcoholic individuals. Electrophysiological and quantitative synaptomics techniques were used to test the hypothesis that heavy drinking produces neuroadaptations in the macaque OFC. Integrative bioinformatics and reverse genetic approaches were used to identify and validate synaptic proteins with novel links to heavy drinking in BXD mice. In drinking monkeys, evoked firing of OFC pyramidal neurons was reduced, whereas the amplitude and frequency of postsynaptic currents were enhanced compared with controls. Bath application of alcohol reduced evoked firing in neurons from control monkeys, but not drinking monkeys. Profiling of the OFC synaptome identified alcohol-sensitive proteins that control glutamate release (e.g., SV2A, synaptogyrin-1) and postsynaptic signaling (e.g., GluA1, PRRT2) with no changes in synaptic GABAergic proteins. Western blot analysis confirmed the increase in GluA1 expression in drinking monkeys. An exploratory analysis of the OFC synaptome found cross-species genetic links to alcohol intake in discrete proteins (e.g., C2CD2L, DIRAS2) that discriminated between low-and heavy-drinking monkeys. Validation studies revealed that BXD mouse strains with the D allele at the C2cd2l interval drank less alcohol than B allele strains. Thus, by profiling of the OFC synaptome, we identified changes in proteins controlling glutamate release and postsynaptic signaling and discovered several proteins related to heavy drinking that have potential as novel targets for treating alcohol use disorder.

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Section: Methodsmentioning

confidence: 88%

Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques

Nimitvilai¹,

Uys

Woodward

et al. 2017

J. Neurosci.

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“…Rumination is associated with unhappiness (47) and may be a form of emotionality itself; hyperactivation in this network could contribute to difficulties in emotion regulation in substance and other disorders. Heightened intraregional rACC/vmPFC connectivity has been observed in depression (93), and heightened within-network connectivity has been observed in alcohol disorders (94). Although our theory is more concerned with basal default mode network activity, it is still notable that difficulty “shutting down” the net work has been observed in PTSD (57), ADHD (48), and cocaine disorders (95).…”

Section: Potential Treatment Targetsmentioning

confidence: 99%

Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders

Wilcox¹,

Pommy²,

Adinoff³

2016

AJP

167

126

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Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity.

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“…ANA will include functional MRI-based domain-specific assessments, along with imaging-based measures of brain structure (e.g. volume, morphometry, white matter integrity) and function, e.g., to assess differences in resting state functional connectivity identified in alcohol dependent patients (112). The salience of neuroimaging to ANA is underscored by recent imaging-genetics findings suggesting, for example, differences in neural response to alcohol cues as a function of genotype (113) and genetic modulation of neural connectivity related to nicotine addiction (114) and of resting state functional connectivity in AUD (115).…”

Section: Introductionmentioning

confidence: 99%

Addictions Neuroclinical Assessment: A Neuroscience-Based Framework for Addictive Disorders

Kwako

Momenan

Litten

et al. 2016

Biological Psychiatry

Self Cite

303

278

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This paper proposes a heuristic framework for an Addictions Neuroclinical Assessment (ANA) that incorporates key functional domains derived from the neurocircuitry of addiction. We review how addictive disorders (AD) are presently diagnosed, and the need for new neuroclinical measures to differentiate patients who meet clinical criteria for addiction to the same agent while differing in etiology, prognosis and treatment response. The need for a better understanding of the mechanisms provoking and maintaining addiction, as evidenced by the limitations of current treatments and within-diagnosis clinical heterogeneity, is articulated. In addition, recent changes in the nosology of AD, challenges to current classification systems, and prior attempts to subtype individuals with AD are described. Complementary initiatives, including the Research Domain Criteria (RDoC) project, which have established frameworks for the neuroscience of psychiatric disorders, are discussed. Three domains, executive function, incentive salience, and negative emotionality, tied to different phases in the cycle of addiction, form the core functional elements of AD. Measurement of these domains in epidemiologic, genetic, clinical, and treatment studies will provide the underpinnings for an understanding of cross-population and temporal variation in addictions, shared mechanisms in addictive disorders, impact of changing environmental influences, and gene identification. Finally, we show that it is practical to implement such a deep neuroclinical assessment using a combination of neuroimaging and performance measures. Neuroclinical assessment is key to reconceptualizing the nosology of AD on the basis of process and etiology, an advance that can lead to improved prevention and treatment.

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Model‐free functional connectivity and impulsivity correlates of alcohol dependence: a resting‐state study

Cited by 126 publications

References 31 publications

Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques

Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques

Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders

Addictions Neuroclinical Assessment: A Neuroscience-Based Framework for Addictive Disorders

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