Advertisement

Long-Term Cocaine Self-administration Produces Structural Brain Changes That Correlate With Altered Cognition

      Abstract

      Background

      An enduring question from cross-sectional clinical studies is whether the structural and functional differences often observed between cocaine users and healthy control subjects result from a history of drug use or instead reflect preexisting differences. To assess causality from drug exposure, true predrug baseline imaging and neurocognitive assessments are needed.

      Methods

      We addressed this fundamental question of causality using longitudinal anatomical magnetic resonance imaging and neurocognitive assessments in rhesus macaques. Cognitive tasks employed were stimulus reversal learning as a measure of cognitive flexibility/inhibitory control and delayed match to sample as a measure of visual working memory. Time points examined were before and following 12 months of chronic cocaine (n = 8) or water (n = 6) self-administration. A magnetic resonance imaging–only time point was also obtained following 2 years of forced abstinence.

      Results

      We identified localized patterns of gray matter density (GMD) changes that were largely concordant with cross-sectional clinical studies. These included decreases in orbitofrontal cortex, insula, amygdala, and temporal cortex. There was also a prominent increase in GMD in the caudate putamen. GMD decreases were significantly correlated with cognitive impairments across individuals only in select cortical regions. Following abstinence, changes in GMD in some regions, including the orbitofrontal cortex, insula, and amygdala, were persistent and thus may play an important role in risk of relapse following extended abstinence.

      Conclusions

      Cocaine use is causal in producing regional changes in GMD, and those changes appear to drive cognitive impairments.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ersche K.D.
        • Williams G.B.
        • Robbins T.W.
        • Bullmore E.T.
        Meta-analysis of structural brain abnormalities associated with stimulant drug dependence and neuroimaging of addiction vulnerability and resilience.
        Curr Opin Neurobiol. 2013; 23: 615-624
        • Mackey S.
        • Paulus M.
        Are there volumetric brain differences associated with the use of cocaine and amphetamine-type stimulants?.
        Neurosci Biobehav Rev. 2013; 37: 300-316
        • Goodkind M.
        • Eickhoff S.B.
        • Oathes D.J.
        • Jiang Y.
        • Chang A.
        • Jones-Hagata L.B.
        • et al.
        Identification of a common neurobiological substrate for mental illness.
        JAMA Psychiatry. 2015; 72: 305-315
        • Mackey S.
        • Allgaier N.
        • Chaarani B.
        • Spechler P.
        • Orr C.
        • Bunn J.
        • et al.
        Mega-analysis of gray matter volume in substance dependence: General and substance-specific regional effects.
        Am J Psychiatry. 2019; 176: 119-128
        • Franklin T.R.
        • Acton P.D.
        • Maldjian J.A.
        • Gray J.D.
        • Croft J.R.
        • Dackis C.A.
        • et al.
        Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients.
        Biol Psychiatry. 2002; 51: 134-142
        • Potvin S.
        • Stavro K.
        • Rizkallah E.
        • Pelletier J.
        Cocaine and cognition: A systematic quantitative review.
        J Addict Med. 2014; 8: 368-376
        • Ersche K.D.
        • Barnes A.
        • Jones P.S.
        • Morein-Zamir S.
        • Robbins T.W.
        • Bullmore E.T.
        Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence.
        Brain. 2011; 134: 2013-2024
        • Sim M.E.
        • Lyoo I.K.
        • Streeter C.C.
        • Covell J.
        • Sarid-Segal O.
        • Ciraulo D.A.
        • et al.
        Cerebellar gray matter volume correlates with duration of cocaine use in cocaine-dependent subjects.
        Neuropsychopharmacology. 2007; 32: 2229-2237
        • Alia-Klein N.
        • Parvaz M.A.
        • Woicik P.A.
        • Konova A.B.
        • Maloney T.
        • Shumay E.
        • et al.
        Gene x disease interaction on orbitofrontal gray matter in cocaine addiction.
        Arch Gen Psychiatry. 2011; 68: 283-294
        • Connolly C.G.
        • Bell R.P.
        • Foxe J.J.
        • Garavan H.
        Dissociated grey matter changes with prolonged addiction and extended abstinence in cocaine users.
        PLoS One. 2013; 8e59645
        • Hanlon C.A.
        • Dufault D.L.
        • Wesley M.J.
        • Porrino L.J.
        Elevated gray and white matter densities in cocaine abstainers compared to current users.
        Psychopharmacology (Berl). 2011; 218: 681-692
        • Schwartz D.L.
        • Mitchell A.D.
        • Lahna D.L.
        • Luber H.S.
        • Huckans M.S.
        • Mitchell S.H.
        • et al.
        Global and local morphometric differences in recently abstinent methamphetamine-dependent individuals.
        Neuroimage. 2010; 50: 1392-1401
        • Kim S.J.
        • Lyoo I.K.
        • Hwang J.
        • Chung A.
        • Hoon Sung Y.
        • Kim J.
        • et al.
        Prefrontal grey-matter changes in short-term and long-term abstinent methamphetamine abusers.
        Int J Neuropsychopharmacol. 2006; 9: 221-228
        • Parvaz M.A.
        • Moeller S.J.
        • d’Oleire Uquillas F.
        • Pflumm A.
        • Maloney T.
        • Alia-Klein N.
        • et al.
        Prefrontal gray matter volume recovery in treatment-seeking cocaine-addicted individuals: A longitudinal study.
        Addict Biol. 2017; 22: 1391-1401
        • Porter J.N.
        • Olsen A.S.
        • Gurnsey K.
        • Dugan B.P.
        • Jedema H.P.
        • Bradberry C.W.
        Chronic cocaine self-administration in rhesus monkeys: Impact on associative learning, cognitive control, and working memory.
        J Neurosci. 2011; 31: 4926-4934
        • Ersche K.D.
        • Roiser J.P.
        • Robbins T.W.
        • Sahakian B.J.
        Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans.
        Psychopharmacology (Berl). 2008; 197: 421-431
        • Croxson P.L.
        • Johansen-Berg H.
        • Behrens T.E.
        • Robson M.D.
        • Pinsk M.A.
        • Gross C.G.
        • et al.
        Quantitative investigation of connections of the prefrontal cortex in the human and macaque using probabilistic diffusion tractography.
        J Neurosci. 2005; 25: 8854-8866
        • Mandeville J.B.
        • Choi J.K.
        • Jarraya B.
        • Rosen B.R.
        • Jenkins B.G.
        • Vanduffel W.
        fMRI of cocaine self-administration in macaques reveals functional inhibition of basal ganglia.
        Neuropsychopharmacology. 2011; 36: 1187-1198
        • Bradberry C.W.
        Cocaine sensitization and dopamine mediation of cue effects in rodents, monkeys, and humans: Areas of agreement, disagreement, and implications for addiction.
        Psychopharmacology (Berl). 2007; 191: 705-717
        • Narendran R.
        • Martinez D.
        Cocaine abuse and sensitization of striatal dopamine transmission: A critical review of the preclinical and clinical imaging literature.
        Synapse. 2008; 62: 851-869
        • Beveridge T.J.
        • Gill K.E.
        • Hanlon C.A.
        • Porrino L.J.
        Review. Parallel studies of cocaine-related neural and cognitive impairment in humans and monkeys.
        Philos Trans R Soc Lond B Biol Sci. 2008; 363: 3257-3266
        • Jedema H.P.
        • Gianaros P.J.
        • Greer P.J.
        • Kerr D.D.
        • Liu S.
        • Higley J.D.
        • et al.
        Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission.
        Mol Psychiatry. 2010; 15 (446): 512-522
        • Reuter M.
        • Fischl B.
        Avoiding asymmetry-induced bias in longitudinal image processing.
        Neuroimage. 2011; 57: 19-21
        • Tustison N.J.
        • Avants B.B.
        • Cook P.A.
        • Zheng Y.
        • Egan A.
        • Yushkevich P.A.
        • et al.
        N4ITK: Improved N3 bias correction.
        IEEE Trans Med Imaging. 2010; 29: 1310-1320
        • Zhang Y.
        • Brady M.
        • Smith S.
        Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm.
        IEEE Trans Med Imaging. 2001; 20: 45-57
        • Reuter M.
        • Schmansky N.J.
        • Rosas H.D.
        • Fischl B.
        Within-subject template estimation for unbiased longitudinal image analysis.
        Neuroimage. 2012; 61: 1402-1418
        • Rohlfing T.
        • Kroenke C.D.
        • Sullivan E.V.
        • Dubach M.F.
        • Bowden D.M.
        • Grant K.A.
        • et al.
        The INIA19 template and NeuroMaps atlas for primate brain image parcellation and spatial normalization.
        Front Neuroinform. 2012; 6: 27
        • Winkler A.M.
        • Ridgway G.R.
        • Douaud G.
        • Nichols T.E.
        • Smith S.M.
        Faster permutation inference in brain imaging.
        Neuroimage. 2016; 141: 502-516
        • Winkler A.M.
        • Ridgway G.R.
        • Webster M.A.
        • Smith S.M.
        • Nichols T.E.
        Permutation inference for the general linear model.
        Neuroimage. 2014; 92: 381-397
        • Smith S.M.
        • Nichols T.E.
        Threshold-free cluster enhancement: Addressing problems of smoothing, threshold dependence and localisation in cluster inference.
        Neuroimage. 2009; 44: 83-98
        • Porter J.N.
        • Minhas D.
        • Lopresti B.J.
        • Price J.C.
        • Bradberry C.W.
        Altered cerebellar and prefrontal cortex function in rhesus monkeys that previously self-administered cocaine.
        Psychopharmacology (Berl). 2014; 231: 4211-4218
        • Gonzalez R.C.
        • Woods R.E.
        Digital Imaging Processing.
        4th ed. Pearson, London2018
        • Geng X.
        • Hu Y.
        • Gu H.
        • Salmeron B.J.
        • Adinoff B.
        • Stein E.A.
        • et al.
        Salience and default mode network dysregulation in chronic cocaine users predict treatment outcome.
        Brain. 2017; 140: 1513-1524
        • Bartzokis G.
        • Beckson M.
        • Lu P.H.
        • Edwards N.
        • Rapoport R.
        • Wiseman E.
        • et al.
        Age-related brain volume reductions in amphetamine and cocaine addicts and normal controls: Implications for addiction research.
        Psychiatry Res. 2000; 98: 93-102
        • Jacobsen L.K.
        • Giedd J.N.
        • Gottschalk C.
        • Kosten T.R.
        • Krystal J.H.
        Quantitative morphology of the caudate and putamen in patients with cocaine dependence.
        Am J Psychiatry. 2001; 158: 486-489
        • Mackey S.
        • Stewart J.L.
        • Connolly C.G.
        • Tapert S.F.
        • Paulus M.P.
        A voxel-based morphometry study of young occasional users of amphetamine-type stimulants and cocaine.
        Drug Alcohol Depend. 2014; 135: 104-111
        • Vaquero L.
        • Camara E.
        • Sampedro F.
        • Perez de Los Cobos J.
        • Batlle F.
        • Fabregas J.M.
        • et al.
        Cocaine addiction is associated with abnormal prefrontal function, increased striatal connectivity and sensitivity to monetary incentives, and decreased connectivity outside the human reward circuit.
        Addict Biol. 2017; 22: 844-856
        • Kroenke C.D.
        • Rohlfing T.
        • Park B.
        • Sullivan E.V.
        • Pfefferbaum A.
        • Grant K.A.
        Monkeys that voluntarily and chronically drink alcohol damage their brains: A longitudinal MRI study.
        Neuropsychopharmacology. 2014; 39: 823-830
        • Fellows L.K.
        • Farah M.J.
        Ventromedial frontal cortex mediates affective shifting in humans: Evidence from a reversal learning paradigm.
        Brain. 2003; 126: 1830-1837
        • Izquierdo A.
        • Brigman J.L.
        • Radke A.K.
        • Rudebeck P.H.
        • Holmes A.
        The neural basis of reversal learning: An updated perspective.
        Neuroscience. 2017; 345: 12-26
        • Osada T.
        • Ohta S.
        • Ogawa A.
        • Tanaka M.
        • Suda A.
        • Kamagata K.
        • et al.
        An essential role of the intraparietal sulcus in response inhibition predicted by parcellation-based network.
        J Neurosci. 2019; 39: 2509-2521
        • Olsen R.K.
        • Nichols E.A.
        • Chen J.
        • Hunt J.F.
        • Glover G.H.
        • Gabrieli J.D.
        • et al.
        Performance-related sustained and anticipatory activity in human medial temporal lobe during delayed match-to-sample.
        J Neurosci. 2009; 29: 11880-11890
        • Schon K.
        • Ross R.S.
        • Hasselmo M.E.
        • Stern C.E.
        Complementary roles of medial temporal lobes and mid-dorsolateral prefrontal cortex for working memory for novel and familiar trial-unique visual stimuli.
        Eur J Neurosci. 2013; 37: 668-678
        • Wilson F.A.
        • Scalaidhe S.P.
        • Goldman-Rakic P.S.
        Dissociation of object and spatial processing domains in primate prefrontal cortex.
        Science. 1993; 260: 1955-1958
        • Lawrence N.S.
        • Ross T.J.
        • Hoffmann R.
        • Garavan H.
        • Stein E.A.
        Multiple neuronal networks mediate sustained attention.
        J Cogn Neurosci. 2003; 15: 1028-1038
        • Buffalo E.A.
        • Ramus S.J.
        • Squire L.R.
        • Zola S.M.
        Perception and recognition memory in monkeys following lesions of area TE and perirhinal cortex.
        Learn Mem. 2000; 7: 375-382
        • Porter J.N.
        • Gurnsey K.
        • Jedema H.P.
        • Bradberry C.W.
        Latent vulnerability in cognitive performance following chronic cocaine self-administration in rhesus monkeys.
        Psychopharmacology (Berl). 2013; 226: 139-146
        • Kriegeskorte N.
        • Simmons W.K.
        • Bellgowan P.S.
        • Baker C.I.
        Circular analysis in systems neuroscience: The dangers of double dipping.
        Nat Neurosci. 2009; 12: 535-540
        • Zilverstand A.
        • Huang A.S.
        • Alia-Klein N.
        • Goldstein R.Z.
        Neuroimaging impaired response inhibition and salience attribution in human drug addiction: A systematic review.
        Neuron. 2018; 98: 886-903
        • Garavan H.
        Insula and drug cravings.
        Brain Struct Funct. 2010; 214: 593-601
        • Goldstein R.Z.
        • Craig A.D.
        • Bechara A.
        • Garavan H.
        • Childress A.R.
        • Paulus M.P.
        • et al.
        The neurocircuitry of impaired insight in drug addiction.
        Trends Cogn Sci. 2009; 13: 372-380
        • Chang L.
        • Ernst T.
        • Strickland T.
        • Mehringer C.M.
        Gender effects on persistent cerebral metabolite changes in the frontal lobes of abstinent cocaine users.
        Am J Psychiatry. 1999; 156: 716-722
        • DePoy L.M.
        • Zimmermann K.S.
        • Marvar P.J.
        • Gourley S.L.
        Induction and blockade of adolescent cocaine-induced habits.
        Biol Psychiatry. 2017; 81: 595-605
        • Radley J.J.
        • Anderson R.M.
        • Cosme C.V.
        • Glanz R.M.
        • Miller M.C.
        • Romig-Martin S.A.
        • et al.
        The contingency of cocaine administration accounts for structural and functional medial prefrontal deficits and increased adrenocortical activation.
        J Neurosci. 2015; 35: 11897-11910
        • Selvas A.
        • Coria S.M.
        • Kastanauskaite A.
        • Fernaud-Espinosa I.
        • DeFelipe J.
        • Ambrosio E.
        • et al.
        Rat-strain dependent changes of dendritic and spine morphology in the hippocampus after cocaine self-administration.
        Addict Biol. 2017; 22: 78-92
        • Clark K.H.
        • Wiley C.A.
        • Bradberry C.W.
        Psychostimulant abuse and neuroinflammation: Emerging evidence of their interconnection.
        Neurotox Res. 2013; 23: 174-188
        • Little K.Y.
        • Ramssen E.
        • Welchko R.
        • Volberg V.
        • Roland C.J.
        • Cassin B.
        Decreased brain dopamine cell numbers in human cocaine users.
        Psychiatry Res. 2009; 168: 173-180
        • Scofield M.D.
        • Li H.
        • Siemsen B.M.
        • Healey K.L.
        • Tran P.K.
        • Woronoff N.
        • et al.
        Cocaine self-administration and extinction leads to reduced glial fibrillary acidic protein expression and morphometric features of astrocytes in the nucleus accumbens core.
        Biol Psychiatry. 2016; 80: 207-215
        • Zhang Q.
        • You J.
        • Volkow N.D.
        • Choi J.
        • Yin W.
        • Wang W.
        • et al.
        Chronic cocaine disrupts neurovascular networks and cerebral function: Optical imaging studies in rodents.
        J Biomed Opt. 2016; 21: 26006
        • Wang Z.
        • Suh J.
        • Duan D.
        • Darnley S.
        • Jing Y.
        • Zhang J.
        • et al.
        A hypo-status in drug-dependent brain revealed by multi-modal MRI.
        Addict Biol. 2017; 22: 1622-1631
        • Adinoff B.
        • Braud J.
        • Devous M.D.
        • Harris T.S.
        Caudolateral orbitofrontal regional cerebral blood flow is decreased in abstinent cocaine-addicted subjects in two separate cohorts.
        Addict Biol. 2012; 17: 1001-1012
        • Volkow N.D.
        • Mullani N.
        • Gould K.L.
        • Adler S.
        • Krajewski K.
        Cerebral blood flow in chronic cocaine users: A study with positron emission tomography.
        Br J Psychiatry. 1988; 152: 641-648

      Linked Article

      • Brain Structural Consequences of Chronic Cocaine Exposure and Their Effects on Behavior
        Biological PsychiatryVol. 89Issue 4
        • Preview
          Cocaine is a powerful addictive stimulant and its abuse is highly prevalent in young adults. Unfortunately, as of today no pharmacological treatment is available and behavioral interventions tend to have high relapse rates. Advancing the knowledge of brain structures that are susceptible to chronic cocaine exposure, the functional consequences of such structural alterations, and the neurobiological mechanisms that underlie the long-lasting risk of relapse in cocaine-dependent populations could contribute toward understanding the neurocircuitry involved in this disorder.
        • Full-Text
        • PDF