Full Length ArticleRegular cannabis and alcohol use is associated with resting-state time course power spectra in incarcerated adolescents
Introduction
Adolescence is a period of significant growth and developmental change. Psychologically, one of the most marked changes may be the rise in risk-taking behavior, which places the adolescent at an increased risk for antisocial behaviors, such as substance use. In 2013, 34.9% of United States high-school students reported to have drunk alcohol in the last month, while 23.4% reported the use of cannabis (Kann et al., 2014). In adolescent detainees, these numbers are even higher, with 41–47% of youth reporting heavy alcohol use and 36–48% reporting use of cannabis (Ewing et al., 2015). Paradoxically, as the adolescent brain undergoes major changes in synaptic receptors density as well as in myelination (Crews et al., 2007), it may be particularly vulnerable to the effects of substance exposure. Elucidating the effects of substance use on the adolescent brain may provide important information for prevention, the development of intervention programs, and policy-making.
Both cannabis and alcohol are believed to have widespread effects on the brain. The main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), binds to endogenous cannabinoid receptor-1 (CB1). CB1 receptors are widely distributed throughout the brain, but are especially concentrated in the cerebellum, prefrontal cortex, striatum, amygdala, and hippocampus (Hirvonen et al., 2012), and play a role in neurotransmitter release and concentrations across neural systems. Cannabinoid receptor density is also greater in children and adolescents than in adults (Glass et al., 1997). By affecting glutamate and gamma-aminobutyric acid (GABA) systems, THC may interfere with brain maturational processes (Bossong and Niesink, 2010). Exposing the cellular and molecular targets for alcohol's actions has proven more challenging. However, like cannabis, alcohol is believed to affect many neurotransmitter systems in the brain (Paul, 2006). Three important neurotransmitter systems that undergo substantial changes during adolescence and are affected by alcohol consumption are dopamine, glutamine, and GABA (Hiller-Sturmhofel and Swartzwelder, 2004).
Cannabis and alcohol use during adolescence have been associated with both immediate and long-term outcomes that include disruptions in task-relevant neural activity and small or no effects on cognition (Gonzalez et al., 2012, Harvey et al., 2007, Jacobsen et al., 2007, Jager et al., 2010, Lane et al., 2007, Tapert et al., 2007, Tait et al., 2011). Structural magnetic resonance imaging (MRI) analyses suggest that adolescent cannabis use may be associated with decreased gray matter volume in widespread regions of the brain, such as the prefrontal cortex, amygdala, and hippocampus (Churchwell et al., 2010, Cousijn et al., 2012, Filbey et al., 2014, Yucel et al., 2006). Youth who drink alcohol show decreased brain volume or cortical thickness in the frontal, temporal, and parietal cortex, and hippocampus (Nagel et al., 2005, Luciana et al., 2013, Squeglia et al., 2014, Squeglia et al., 2015). Generally, earlier initiation of use and more frequent use have been associated with poorer outcomes (Buchy et al., 2015, Pope et al., 2003), and while some studies suggest that effects of alcohol and cannabis use decrease after prolonged periods of abstincence (Fortier et al., 2014, Hanson et al., 2010, Jacobus et al., 2012), other studies suggest long-lasting effects of adolescent alcohol and cannabis use (Ashtari et al., 2011, van Eijk et al., 2013). However, study results vary widely and await replication.
Functional connectivity, defined as the relation between the neuronal activation patterns of anatomically separated brain regions (Aertsen et al., 1989), describes the organization, inter-relationship and integrated performance of functionally coupled brain regions (Rogers et al., 2008). Most commonly, studies on functional connectivity describe the temporal correlation between two or more regions, or compare the spatial maps of resting-state networks. This latter measure examines the correspondence of the network’s time course and the time course of each voxel in a network (Balsters et al., 2013), thus providing a measure of a region’s strength of connectivity within a given network. The literature on cannabis use mostly describes increased functional connectivity in adult or adolescent cannabis users compared to controls in (regions of) the default mode network (DMN), salience network, and executive control network (ECN) (Cheng et al., 2014, Filbey et al., 2014, Harding et al., 2012, Houck et al., 2013, Pujol et al., 2014). However, more recently, several studies have reported negative associations between cannabis use and functional connectivity (Camchong et al., 2016, Orr et al., 2013, Peters et al., 2015).
Alcohol use has also been shown to be associated with functional connectivity. Both weaker and stronger functional connectivity have been reported in the DMN, salience network, subcortical reward network and ECN (Weiland et al., 2014, Zhu et al., 2017), as well as stronger functional connectivity in the left frontoparietal network (Jansen et al., 2015) basal ganglia network and primary visual network (Weilandt et al., 2014). Moreover, disturbances in frontoparietal connectivity have been observed even in substance-naïve youth with a family history of alcohol (Wetherill et al., 2012), which suggest that weaker frontoparietal connectivity may be a neurobiological marker for alcohol use disorders. Thus, both alcohol and cannabis use appear to be associated to functional connectivity, however, studies are inconclusive whether associations are positive or negative.
Although described less frequently, functional connectivity can also be examined by measuring time course power spectra. The MR signal is dominated by oscillations in the 0.0–0.1 Hz frequency band (Cordes et al., 2001). The magnitude of these oscillations may differ per brain region and per person, and thus can be examined as a marker of individual differences. The time course power spectra reflect the degree of fluctuation in amplitude of the intrinsic activity within the network (Calhoun et al., 2011). The time courses of the different networks can also be correlated, resulting in a measure called functional network connectivity (FNC, Arbabshirani et al., 2013). The present study will examine associations between alcohol and cannabis use and network spatial map, network time course power spectra and functional network connectivity.
Possibly due to relatively small sample sizes, studies examining substance use and functional connectivity mostly describe associations between a few regions or networks only rather than a comprehensive whole-brain analysis. Moreover, studies that do perform whole-brain analyses generally only assess differences in network spatial maps. The present study describes the results of a dose-response analysis of the association between duration of regular (comorbid) cannabis and alcohol use and whole-brain resting-state functional connectivity in a large sample of male juvenile delinquents, whom due to their imprisonment were abstinent. The majority of the sample has been dependent on cannabis or alcohol, many on both. We therefore expected that cannabis and alcohol use would be associated with widespread differences in functional connectivity despite current abstinence. In the spatial map domain, both cannabis and alcohol use are expected to affect the DMN, salience network, and ECN. Moreover, we hypothesize alcohol to be associated with frontoparietal network connectivity. However, as time course power spectra and between network connectivity are less frequently studied, we have no specific hypotheses regarding these domains.
Section snippets
Participants
The present sample was drawn from the NIMH-funded Southwest Advanced Neuroimaging Cohort, Youth sample (SWANC-Y), collected between June 2007, and May 2011 in a maximum-security facility in New Mexico and from ongoing (2011-15) research at a youth detention facility in Wisconsin. This research was approved by the University of New Mexico Human Research Review Committee. Both youth and parent/guardian provided written informed assent/consent. Participants were compensated comparable to the pay
Results
We performed a 30 component GICA using resting-state functional MRI (rs fMRI) data from 201 participants. Based on visual inspection of the spatial maps and power spectra, 15 components were identified as ventricular, vascular, susceptibility or motion-related artifacts (Fig. S1). The 15 remaining components corresponded to known resting-state networks and are shown in Fig. S2. Coordinates of their peak activation are provided in Table S1. Fig. S3 shows the FNC. The ICA parcellation resulted in
Discussion
The present study examined the association between duration of cannabis and alcohol use and resting-state functional connectivity in a large sample of male juvenile delinquents. The majority of participants have met criteria for cannabis and/or alcohol dependence. However, due to their detention, all participants were in forced abstinence. Although hypothesized, no associations with network spatial maps were found. However, cannabis and alcohol use had widespread yet distinct associations with
Conclusion
Although no associations between cannabis and alcohol use and network spatial maps have been found, we have identified specific patterns of decreased coherent network activity (spectral power analysis) and FNC in relation to duration of cannabis and alcohol use. These findings may point towards less effective communication between brain regions/networks. As the analysis of spectral power is relatively uncommon in substance use research, our findings provide important information for hypothesis
Contributions
Sandra Thijssen: conception, analysis, interpretation and writing
Barnaly Rashid: analysis
Shruti Gopal: analysis
Prashanth Nyalakanti: analysis
Vince D. Calhoun: analysis, interpretation
Kent A. Kiehl: conception, analysis, interpretation
All authors approved of the final manuscript.
Role of funding source
Data collection was funded by NIMH; 1 R01 MH071896–01 (PI: Kiehl) and NICHD: 1R01HD082257-01 (PI: Kiehl). Thijssen was funded by a European Research Council grant (ERC AdG 669249) awarded to Marian J. Bakermans-Kranenburg.
Conflict of interest
No conflict declared.
References (86)
- et al.
Medial temporal structures and memory functions in adolescents with heavy cannabis use
J. Psychiatr. Res.
(2011) - et al.
Changes in resting connectivity with age: a simultaneous electroencephalogram and functional magnetic resonance imaging investigation
Neurobiol. Aging
(2013) - et al.
Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia
Prog. Neurobiol.
(2010) - et al.
A review of group ICA for fMRI data and ICA for joint inference of imaging, genetic, and ERP data
Neuroimage
(2009) - et al.
Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility
Pharmacol. Biochem. Behav.
(2014) - et al.
Grey matter alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls
Neuroimage
(2012) - et al.
Adolescent cortical development: a critical period of vulnerability for addiction
Pharmacol. Biochem. Behav.
(2007) - et al.
Motion correction algorithms may create spurious brain activations in the absence of subject motion
Neuroimage
(2001) - et al.
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
Neuroimage
(2002) - et al.
Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain
Neurosci
(1997)
Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence
Addict. Behav.
Functional correlates of verbal memory deficits emerging during nicotine withdrawal in abstinent adolescent cannabis users
Biol. Psychiatry
A method for functional network connectivity among spatially independent resting-state components in schizophrenia
Neuroimage
Resting state connectivity in alcohol dependent patients and the effect of repetitive transcranial magnetic stimulation
Eur. Neuropsychopharmacol.
Amplitude low-frequency oscillation abnormalities in the heroin users: a resting state fMRI study
Neuroimage
Schedule for affective disorders and schizophrenia for school-age children present and lifetime version (K-SADS-PL): initial reliability and validity data
J. Am. Acad. Child Adolesc. Psychiatry
Response perseveration and adaptation in heavy marijuana-smoking adolescents
Addict. Behav.
Sex differences in thickness, and folding developments throughout the cortex
Neuroimage
Reduced hippocampal volume among adolescents with alcohol use disorders without psychiatric comorbidity
Psychiatry Res. Neuroimag.
Default mode network abnormalities in bipolar disorder and schizophrenia
Psychiatry Res. Neuroimag.
The link between testosterone and amygdala-orbitofrontal cortex connectivity in adolescent alcohol use
Psychoneuroendocrinol
White matter microstructural recovery with abstinence and decline with relapse in alcohol dependence interacts with normal ageing: a controlled longitudinal DTI study
Lancet Psychiatry
Early-onset cannabis use and cognitive deficits: what is the nature of the association?
Drug Alcohol Depend.
Functional connectivity alterations in brain networks relevant to self-awareness in chronic cannabis users
J. Psychiatr. Res.
Brain volume reductions in adolescent heavy drinkers
Dev. Cogn. Neurosci.
A selective insular perfusion deficit contributes to compromised salience network connectivity in recovering alcoholic men
Biol. Psychiatry
Earlier adolescent substance use onset predicts stronger connectivity between reward and cognitive control brain networks
Dev. Cogn. Neurosci.
Frontoparietal connectivity in substance-nave youth with and without a family history of alcoholism
Brain Res.
Cannabis, cigarettes, and their co-occurring use: disentangling differences in default mode network functional connectivity
Drug Alcohol Depend.
Acute effects of alcohol on the human brain: a resting-state fmri study
BioMed Res. Int.
Cannabinoid cb1 receptor agonists do not decrease, but may increase acoustic trauma-induced tinnitus in rats
Front. Neurol.
An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: Fractional ALFF
J. Neurosci. Method
Dynamics of neuronal firing correlation − modulation of effective connectivity
J. Neurophysiol.
A baseline for the multivariate comparison of resting-state networks
Front. Syst. Neurosci.
The brain's default network and its adaptive role in internal mentation
Neuroscientist
Functional network connectivity during rest and task conditions: A comparative study
Hum. Brain Mapp.
An information maximization approach to blind separation and blind deconvolution
Neural Comput.
Default mode network in the effects of Delta9-Tetrahydrocannabinol (THC) on human executive function
PLoS One
Evaluating the impact of cannabis use on thalamic connectivity in youth at clinical high risk of psychosis
BMC Psychiatry
Multisubject independent component analysis of fMRI: a decade of intrinsic networks, default mode, and neurodiagnostic discovery
IEEE Rev. Biomed. Eng.
A method for making group inferences using independent component analysis of functional MRI data: exploring the visual system
Neuroimage
Exploring the psychosis functional connectome: aberrant intrinsic networks in schizophrenia and bipolar disorder
Front. Psychiatry
Intrinsic functional and structural networks in schizophrenia bipolar disorder, and healthy controls
Biol. Psychiatry
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2018, NeuroImageCitation Excerpt :This finding may suggest that the effect of iron on coherence is perhaps more lasting than its effect on SMs. This hypothesis finds support from a study that showed that alcohol and substance use were associated with widespread differences in resting-state power spectra, with no impact on SMs (Thijssen et al., 2017). Moreover, a number of previous studies have shown that the Amplitude of Low Frequency Fluctuation (ALFF), which corresponds to the square root of the power spectra, is a more sensitive measure compared to its corresponding conventional functional connectivity (Zuo et al., 2010; Wang et al., 2012; Tadayonnejad et al., 2015).
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