48 research outputs found
How Acute and Chronic Alcohol Consumption Affects Brain Networks: Insights from Multimodal Neuroimaging
Backgroundâ
Multimodal imaging combining 2 or more techniques is becoming increasingly
important because no single imaging approach has the capacity to elucidate all clinically relevant
characteristics of a network.
Methodsâ
This review highlights recent advances in multimodal neuroimaging (i.e., combined
use and interpretation of data collected through magnetic resonance imaging [MRI], functional
MRI, diffusion tensor imaging, positron emission tomography, magnetoencephalography, MR
perfusion, and MR spectroscopy methods) that leads to a more comprehensive understanding of
how acute and chronic alcohol consumption affect neural networks underlying cognition, emotion,
reward processing, and drinking behavior.
Resultsâ
Several innovative investigators have started utilizing multiple imaging approaches
within the same individual to better understand how alcohol influences brain systems, both during
intoxication and after years of chronic heavy use.
Conclusionsâ
Their findings can help identify mechanism-based therapeutic and
pharmacological treatment options, and they may increase the efficacy and cost effectiveness of
such treatments by predicting those at greatest risk for relapse
From a systems view to spotting a hidden island : A narrative review implicating insula function in alcoholism
Excessive use of alcohol promotes the development of alcohol addiction, but the understanding of how alcohol induced brain alterations lead to addiction remains limited. To further this understanding, we adopted an unbiased discovery strategy based on the principles of systems medicine. We used functional magnetic resonance imaging data from patients and animal models of alcohol addiction-like behaviors, and developed mathematical models of the 'relapse-prone' network states to identify brain sites and functional networks that can be selectively targeted by therapeutic interventions. Our systems level, non-local, and largely unbiased analyses converged on a few well-defined brain regions, with the insula emerging as one of the most consistent findings across studies. In proof-of-concept experiments we were able to demonstrate that it is possible to guide network dynamics towards increased resilience in animals but an initial translation into a clinical trial targeting the insula failed. Here, in a narrative review, we summarize the key experiments, methodological developments and knowledge gained from this complete round of a discovery cycle moving from identification of 'relapse-prone' network states in humans and animals to target validation and intervention trial. Future concerted efforts are necessary to gain a deeper understanding of insula function a in a state-dependent, circuit-specific and cell population perspective, and to develop the means for insula-directed interventions, before therapeutic targeting of this structure may become possible.Peer reviewe
Dopamine-Mediated Alterations in Brain-Wide Functional Dynamics Measured by fMRI
Drug addiction is a complex, multifaceted disease characterized by compulsive drug-seeking and drug-taking behavior despite adverse consequences. In accordance with its complex nature, several neural systems are likely to be dysregulated to promote maladaptive behaviors associated with addiction. For instance, dopaminergic signaling within the mesolimbic dopamine (DA) system is thought to be critical for reward prediction, an adaptive process that likely goes awry in addiction. While it is well known that DA release events occur in mesolimbic terminal fields such as the nucleus accumbens (NAc) in response to reward predictive cues, including those associated with drugs of abuse, how DA release events affect network adaptation across the entire brain has largely been unexplored. To address this, we selectively activated ventral tegmental area (VTA) dopaminergic (THVTA) neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging (fMRI). We demonstrated DAergic modulation activates several anatomically distinct regions throughout the brain, many of which receive little to no direct dopaminergic input. We also showed that explicit pairing of midbrain dopamine neuron activity and a sensory stimulus can dramatically enhance the brain-wide representation of that specific sensory stimulus. Next, since drugs of abuse increase extracellular DA in the mesolimbic pathway of the brain, we utilized a rodent model of addiction to explore whether functional connectivity is altered after self-administration of cocaine. We found that cocaine self-administration orchestrates dynamic shifts in functional connectivity across many anatomically defined neuronal network nodes. Overall, these findings suggest that DA not only controls plasticity in direct target regions, but may effectively modulate brain-wide network plasticity as well. This research may provide critical insight into the circuit-level maladaptations that underlie compulsive drug-seeking behavior, and the chronic cycles of abstinence and relapse that characterize addiction in humans.Doctor of Philosoph
Anterior insula stimulation suppresses appetitive behavior while inducing forebrain activation in alcohol-preferring rats
The anterior insular cortex plays a key role in the representation of interoceptive effects of drug and natural rewards and their integration with attention, executive function, and emotions, making it a potential target region for intervention to control appetitive behaviors. Here, we investigated the effects of chemogenetic stimulation or inhibition of the anterior insula on alcohol and sucrose consumption. Excitatory or inhibitory designer receptors (DREADDs) were expressed in the anterior insula of alcohol-preferring rats by means of adenovirus-mediated gene transfer. Rats had access to either alcohol or sucrose solution during intermittent sessions. To characterize the brain network recruited by chemogenetic insula stimulation we measured brain-wide activation patterns using pharmacological magnetic resonance imaging (phMRI) and c-Fos immunohistochemistry. Anterior insula stimulation by the excitatory Gq-DREADDs significantly attenuated both alcohol and sucrose consumption, whereas the inhibitory Gi-DREADDs had no effects. In contrast, anterior insula stimulation failed to alter locomotor activity or deprivation-induced water drinking. phMRI and c-Fos immunohistochemistry revealed downstream activation of the posterior insula and medial prefrontal cortex, as well as of the mediodorsal thalamus and amygdala. Our results show the critical role of the anterior insula in regulating reward-directed behavior and delineate an insula-centered functional network associated with the effects of insula stimulation. From a translational perspective, our data demonstrate the therapeutic potential of circuit-based interventions and suggest that potentiation of insula excitability with neuromodulatory methods, such as repetitive transcranial magnetic stimulation (rTMS), could be useful in the treatment of alcohol use disorders.Peer reviewe
Examination of prelimbic cortex and nucleus accumbens core signaling dynamics as a biomarker for cocaine use disorder in a preclinical model
The prelimbic cortex (PrL) and nucleus accumbens (NAc) core, brain regions implicated in higher order processes such as decision making and behavioral flexibility, undergo neuroadaptations following prolonged abstinence from cocaine. Critically, impairments in these processes are also observed in individuals living with substance use disorders (SUDs) and is thought to be linked with these neuroadaptations. Furthermore, there is evidence that using noninvasive brain stimulation (NIBS) techniques may be a promising treatment for SUDs. However, it is not quite clear how these abstinence-related disruptions in PrL and NAc core signaling are related to drug seeking and taking behaviors. Recent work in the Carelli lab has shown that using transcranial alternating current stimulation (tACS, a form of NIBS) was effective in reversing cocaine-induced deficits in PrL-NAc core circuit signaling and restoring impaired behavioral flexibility. The following document consists of three specific aims that used electrophysiological recording methods to investigate signaling dynamics in the PrL and NAc core following prolonged abstinence from cocaine, their relationships to drug seeking and taking behavior, and the effectiveness of tACS to restore cocaine-induced deficits in signaling and behavior.Doctor of Philosoph
Recent Advances in Drug Addiction Research and Clinical Applications
Although it is well-accepted that drug addiction is a major public health concern, how we address it as a society continues to evolve as recent advances in the lab and clinic clarify the nature of the problem and influence our views. This unique collection of eight chapters reviews key findings on the neurobiology and therapeutics of addiction while capturing the diversity of perspectives that shape these concepts, which range from evolutionary biology to psychiatry to the legal system. This book discusses in depth how technological advances have led to important discoveries and how these discoveries, in turn, are increasingly being translated into clinical practice. It also presents avenues for future study that hold promise for the many affected by addiction
The effects of transcranial alternating current stimulation on prelimbic cortex to nucleus accumbens core oscillatory dynamics and cocaine seeking
Prolonged abstinence from cocaine leads to profound changes in brain reward circuitry that contribute to relapse vulnerability. Neuroimaging studies reveal a generalized (resting state) dampening of prefrontal cortex and nucleus accumbens activity which persists after extended periods of abstinence and is linked with impaired executive control in substance use disorder (SUD). Interestingly, however, these same brain regions also show heightened activation to cocaine-related stimuli following prolonged abstinence concomitant with increased drug seeking. Opposing context-dependent shifts in neural signaling following prolonged cocaine abstinence are also observed at the neurocircuit and network level. Given these findings, an emerging strategy for treating SUD uses noninvasive brain stimulation to normalize drug-induced disruptions in brain activity. Our lab recently published data showing the efficacy of transcranial alternating current stimulation (tACS) for reversing cocaine-induced deficits in neural signaling and restoring behavioral flexibility. Three specific aims were completed to investigate the role of the prelimbic cortex to nucleus accumbens core circuit in cocaine-seeking behaviors following short or prolonged abstinence and the feasibility of tACS to modulate oscillatory dynamics and incubated cocaine seeking.Doctor of Philosoph
Cocaine addiction in the rat: alterations in brain functions and novel medications
Cocaine addiction is a chronic mental illness affecting a small subgroup of cocaine users (approx. 18%). Little efforts have been taken so far to understand individual differences in the vulnerability to cocaine addiction; i.e. it is unclear why some users become addicted whereas the majority of them are able to maintain the control over drug-taking and -seeking. Most preclinical studies have not considered the possibility to study individual differences in addiction vulnerability and furthermore may explain the high failure rates of drugs that reach Phase III-IV of clinical trials. Hence, a translational animal model is fundamental to produce meaningful results to the clinic. In this thesis, a DSM-IV/5-based preclinical model of cocaine addiction was used to identify pre-existing vulnerability differences and the changes produced by pathological state of addiction. The so-called 0/3crit animal model consists of training rats for intravenous cocaine self-administration for at least 45 sessions. Thereafter, three main DSM-based addiction behavioral criteria were tested, (1) motivation to take the drug, (2) persistence to seek the drug, and (3) persistence of self-administration despite negative consequences (i.e., application of an electric foot-shock). For each of the three criteria, a score of either 1 or 0 was given to animals performing above or below 60th percentile of the population distribution, respectively. Animals positive for all criteria (3crit) were classified as addicted-like, whereas animals negative for all criteria (0crit) were classified as non-addicted-like/resilient rats.
This thesis had three aims:
(i) Neuroimaging studies in cocaine addicts revealed various structural and functional changes but findings are inconclusive and this may be due to pre-existing features in the function or structure in brains of vulnerable subjects and different drug intake patterns. Based on this, longitudinal studies, particularly in controlled animal models, are warranted. Here a longitudinal translational multimodal neuroimaging study was performed using the 0/3crit animal model of cocaine addiction to investigate pre-existing differences and changes in brains of cocaine addicted-like and non-addicted-like rats.
(ii) Conditioned cocaine cues can trigger craving and relapse. Pavlovian conditioned stimuli can also impact ongoing instrumental behavior, even if the instrumental behavior is acquired independently of Pavlovian conditioning. This process is called Pavlovian-to-Instrumental transfer (PIT). A hypothesis in drug addiction posits that Pavlovian conditioned cues can bias instrumental behavior towards drug seeking and intake and that a more pronounced PIT response occurs in vulnerable subjects. The second aim was therefore to test this hypothesis and to ask whether 3crit rats show a more pronounced PIT response than 0crit rats.
(iii) Pharmacological treatments in cocaine addiction are still lacking. In previous preclinical studies different glutamate receptor antagonists and GABAB agonists such as baclofen, have been tested but either failed in clinical studies or reported severe side effects in pharmacovigilance. Here, different pharmacological approaches were taken: First, the novel GABAB positive allosteric modulator CMPPE was tested in comparison to baclofen in order to produce lesser side effects. Second the NR3A subunit was selectively targeted as an alternative to NMDAR antagonists. Finally, melatonin was tested for normalizing altered circadian rhythmicity in cocaine addiction.
The longitudinal MRI results revealed structural changes in the brains of 3crit and 0crit rats. Grey matter (GM) volume was found to have increased in prelimbic (Prl) and cingulate (Cg) cortices, nucleus accumbens (NAc), caudate putamen (CPu), substantia nigra, and ventral and globus pallidum in the 3crit group, whereas 0crit rats showed no changes in GM volume, except for the CPu, compared to control. Diffusion tensor imaging (DTI) analysis revealed a higher fractional anisotropy in the zona incerta in the 0crit rats compared to 3crit rats. PET results showed higher activity of mPFC and right CPu in the 0crit group compared to controls. Arc expression was significantly reduced in the infralimbic (IFL) cortex in the 3crit group. Salience of conditioned-cues was found similar in 0crit and 3crit rats in the PIT paradigm. Positive allosteric modulator of GABAB receptors and melatonin abolished cue-elicited cocaine-seeking behavior.
In summary, cocaine addiction produced structural changes in brain regions central for motivation and drug rewarding effects in 3crit rats, whereas the addiction resilient rats showed increased volume in brain regions involved in habit behavior as well as an increased in microstructural integrity in a brain area that regulates adaptive behavior. Functional assessments indicated the relevance of the mPFC (Prl and IFL) activity for both controlled or compulsive drug-seeking and âtaking. These results agree with clinical studies, where mPFC function negatively correlates with impulsive behavior in psychostimulant abusers as well as changes were found in brain regions, such as Prl, Cg, CPu, and NAc, that are known to play a role in drug addiction. Moreover, other factors, such as structural and functional changes, instead of Pavlovian or instrumental conditioning may lead to addiction behaviors because salience to conditioned stimuli and learning ability were similar between the groups. And finally, positive allosteric modulator of GABAB receptors and melatonin appears to be promising candidates for medication development in cocaine addiction. The 0/3crit model of cocaine addiction has excellent face validity and can be used to study the underpinning mechanisms that lead to compulsive drug use
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Functional organisation of behavioural inhibitory control mechanisms in cortico-basal ganglia circuitry: implications for stimulant use disorder.
The neural and psychological mechanisms of inhibitory control processes were investigated, focusing on the cortico-basal ganglia circuits in rats and humans. These included behavioural flexibility, âwaitingâ and âstoppingâ impulsivity and involved serial spatial reversal learning task in rodents, and in humans, premature responses in the Monetary Incentive Delay (MID) task and the stop-signal reaction time task. Chapter 2 and Chapter 3 focus on individual differences in behavioural flexibility in rats while Chapter 4, Chapter 5 and Chapter 6 consider how inhibitory control mechanisms are affected by the psychostimulant drug cocaine in both rats and humans.
As reported in Chapter 2, systemic modulation of monoaminergic transmission by monoamine oxidase A (MAO-A) inhibitors enhanced reversal learning performance, selectively by decreasing the lose-shift probability, thereby implicating a role for dopamine, serotonin and noradrenaline in facilitating learning from negative feedback. Resting state functional magnetic resonance imaging (fMRI) revealed enhanced functional connectivity of the orbitofrontal and motor cortices as a correlate of flexible reversal learning performance, consistent with elevated levels of monoamines in these region (Chapter 3). Having clarified the mechanisms underlying behavioural flexibility in rats, Chapter 4 reports that escalation of intravenous cocaine self-administration induces behavioural inflexibility in rats even after a relatively short period of cocaine intake. Computational models, including a reinforced and Bayesian learner, revealed a lack of exploitation of the learned response-outcome relationships in cocaine-exposed rats.
Chapter 5 focused on impulse control in human volunteers, identifying the striatal and cingulo-opercular networks as substrates of impulsive, premature responding in healthy
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volunteers, stimulant-dependent individuals and their unaffected siblings. Loss of impulse control was elicited by different incentives for drug-free participants as opposed to drug users. Drug cues elicited striatal activation and increased premature responses in the stimulant-dependent group compared with the control group. In contrast, the ventral striatum was linked to incentive specific activation to reward anticipation. Task-based fMRI demonstrated that interactions between dorsal striatum and cingulo-opercular âcold cognitionâ networks underlie failures of impulse control in the control, at-risk and stimulant-dependent groups. However, whereas the cingulo-opercular networks were associated with premature responding in all groups, the reward system was activated specifically by the drug incentive cues in the stimulant group, and by monetary incentive cues in the drug-free groups.
Chapter 6 presents evidence that corticostriatal functional and effective connectivity in an overlapping network that includes the anterior cingulate and inferior frontal cortices as well as motor cortex, the subthalamic nucleus and dorsal striatum, is critical to stopping impulse control in both control and cocaine individuals. No stopping efficiency impairments were observed in the cocaine-dependent group. Nevertheless, lower structural corticostriatal connectivity measured using diffusion MRI was associated with response execution impairments in cocaine participants performing a stop-signal reaction time task. Further, response execution was rescued by the selective noradrenaline reuptake inhibitor atomoxetine, which also increased corticostriatal effective connectivity.
Finally, increased impulsivity and behavioural inflexibility seen in stimulant use disorder in Chapter 5 and Chapter 4, respectively, were not observed in the endophenotype at risk for developing stimulant abuse but were rather a consequence of stimulant abuse. These results further clarify the monoaminergic substrates of behavioural flexibility and specify the neural and computational impairments in inhibitory control induced by stimulant dependence.Pinsent Darwin Studentship from the Dept of Physiology, Development and Neuroscienc