Regular articleIncreased frontocerebellar activation in alcoholics during verbal working memory: an fMRI study
Introduction
Chronic alcoholism is linked to a number of adverse changes in brain structure and function. Principal brain areas affected are the frontal lobes and cerebellum and their associated functions (Adams et al., 1993; Gilman et al 1990, Kubota et al 2001, Pfefferbaum et al 1997, Sullivan et al 2003 [for reviews, Oscar-Berman and Hutner (1993), Moselhy et al. (2001), and Sullivan (2000)]. In vivo MRI evidence for regional tissue shrinkage is consistent with postmortem studies that have revealed neuronal loss in frontal lobes Brun and Andersson 2001, Courville 1955, Harper and Kril 1990, Kril et al 1997, Kril and Harper 1989 and reduction of soma size and processes in cerebellar vermis and hemispheres Baker et al 1999, Phillips et al 1987, Torvik and Torp 1986, Victor et al 1989. The cause of these anatomical changes is largely unknown, but recent studies of receptors in the frontal cortex have shown that chronic alcoholism moderately increases the density of the NMDA subtype of glutamate receptors in the frontal cortex (Freund and Anderson, 1996) and decreases the density of benzodiazepine receptors (Freund and Ballinger, 1988), raising the possibility that alcoholism induces chronic neurotoxicity.
Consistent with these anatomical investigations, both functional neuroimaging and neuropsychological studies of alcoholics have revealed alcohol-dependent changes in frontal lobe and cerebellar functions. Neuropsychological tests that measure perseveration and strategy switching [such as the Wisconsin Card Sorting Test (WCST)], behavioral inhibition (such as the Stroop or Hayling Test), verbal fluency (e.g., naming words that begin with a specific letter), and executive function (e.g., manipulation of verbal or spatial information) are sensitive to frontal lobe dysfunction. Three studies have examined the relationship between neuropsychological measures and resting brain function Adams et al 1993, Dao-Castellana et al 1998, Noel et al 2001. These studies found significant correlations between rCBF and neuropsychological performance, suggesting that cognitive operations that depend critically on frontal lobe function may be compromised as a result of chronic alcohol consumption. A logical extension of these studies is to look at how activation of the frontal lobes during a cognitive task may be changed by alcoholism, with the expectation that tasks that exhibit robust frontal lobe activation in functional neuroimaging experiments may be especially sensitive to alcohol-related changes in brain function. Consistent with these expectations, we found in a previous investigation (Pfefferbaum et al., 2001) that brains of alcoholic men exhibited reduced activation relative to control subjects in a spatial working memory task, and similar findings were reported in women (Tapert et al., 2001). The present study focuses on a related cognitive operation that reliably elicits frontal lobe activation in functional neuroimaging studies, verbal working memory. A number of neuroimaging studies have demonstrated in healthy subjects activation of frontal lobes, particularly left frontal regions, during the simple maintenance of verbal information, such as keeping in mind a string of numbers or letters Andreasen et al 1995, Awh et al 1996, Braver et al 1997, Cohen et al 1997, D’Esposito et al 1995, Fiez et al 1996, Jonides et al 1997, Mellers et al 1995, Paulesu et al 1993, Petrides et al 1993, Salmon et al 1996, Schumacher et al 1996, Smith and Jonides 1997. Neuroimaging studies of verbal working memory have also demonstrated reliable activation of contralateral (predominately right) cerebellum Desmond 2001a, Desmond 2001b, Desmond et al 1997, and damage to the right cerebellum has been shown to produce verbal working memory deficits (Silveri et al., 1998). In many cognitive tasks, including verbal working memory, neocortical and contralateral cerebellar activations occur in tandem. Neuroanatomical studies suggest that superior cerebellar hemispheres are well connected to frontal and prefrontal areas via cortico–ponto–cerebellar pathways Brodal 1979, Schmahmann 1996 and may be compromised in chronic alcoholics (cf., Sullivan et al., 2003).
Deficits in verbal working memory in alcoholics are typically most apparent when manipulation of information is required. This raises the question of whether complex manipulation of verbal information is required in order to produce differences between alcoholic and nonalcoholic brain activation, or if differences in activation can be seen even during the simple maintenance of verbal information. The present study examined brain activation differences between alcoholic and nonalcoholic subjects during the maintenance of verbal information. Activation was measured as the difference between high load (six letters) and low load (one letter) of working memory. Based on the changes described above in frontal lobe structure and function occurring from alcoholism, the importance of left frontal structures in articulation, and the crossed nature of cerebrocerebellar circuitry, we hypothesized activation differences between alcoholic and control subjects in left frontal and right cerebellar regions.
Section snippets
Subjects
Subject groups comprised 13 healthy control men and 10 chronically alcoholic men. All subjects underwent screening with structured medical examination and psychiatric interview (Structured Clinical Interview for DSM-IV Diagnosis) and were excluded for history of major psychiatric conditions, significant medical conditions (e.g., chronic hepatic disorder), significant head injury, or loss of consciousness greater than 30 min. The control subjects were recruited from the local community, and the
Group differences in behavioral performance
The two groups did not differ significantly from each other on any of the six measures of performance, i.e., median reaction time for hits and percentage of hits, on the high load, low load, and control conditions. Separate two-group and three-condition ANOVAs for accuracy (percentage of hits) and reaction time failed to yield group effects [accuracy: F(1,21) = 0.71, n.s.; reaction time: F(1,21) = 0.006, n.s.] or group-by-condition interactions [accuracy: F(1,21) = 1.62, n.s.; reaction time: F
Discussion
Consistent with the results of a variety of studies that have measured neuroanatomical, neuropsychological, or resting brain functional abnormalities in frontal lobes of alcoholics, our fMRI study revealed differences in left frontal lobe activity between alcoholics and nonalcoholics while engaged in verbal working memory tasks. This difference was manifested as an increase in the high vs low working memory load in alcoholics relative to controls. A similar group difference in activation was
Acknowledgements
Supported by NIMH (MH60234) and NIAAA (AA10723, AA05965).
References (66)
- et al.
Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke’s encephalopathy
Neuroscience
(1999) - et al.
A parametric study of prefrontal cortex involvement in human working memory
Neuroimage
(1997) The ponto-cerebellar projection in the rhesus monkeyan experimental study with retrograde axonal transport of horseradish peroxidase
Neuroscience
(1979)- et al.
Neuroimaging studies of the cerebellumlanguage, learning and memory
Trends Cogn. Sci.
(1998) - et al.
Decrease of benzodiazepine receptors in frontal cortex of alcoholics
Alcohol
(1988) - et al.
Secondary changes in cerebellar perfusion (diaschisis) in hemiplegia during childhoodSPECT study of 55 children
Pediatr. Neurol.
(1993) - et al.
Cerebral diaschisis following cerebellar hemorrhage
Arch. Phys. Med. Rehabil.
(1997) - et al.
The cerebral cortex is damaged in chronic alcoholics
Neuroscience
(1997) - et al.
The effects of alcohol on prose memory
Physiol. Behav.
(1985) - et al.
Reorganization of frontal systems used by alcoholics for spatial working memoryan fMRI study
Neuroimage
(2001)
PET evidence for an amodal verbal working memory system
Neuroimage
Working memorya view from neuroimaging
Cogn. Psychol.
The prevalence of alcoholic cerebellar atrophya morphometric and histological study of an autopsy material
J. Neurol. Sci.
Differential contributions of motor cortex, basal ganglia, and cerebellum to speech motor controleffects of syllable repetition rate evaluated by fMRI
Neuroimage
Neuropsychological deficits are correlated with frontal hypometabolism in positron emission tomography studies of older alcoholic patients
Alcohol Clin. Exp. Res.
Short-term and long-term verbal memorya positron emission tomography study
Proc. Natl. Acad. Sci. USA
Dissociation of storage and rehearsal in verbal working memoryevidence from positron emission tomography
Psychol. Sci.
Crossed cerebello-cerebral diaschisisa SPECT study
Nucl. Med. Commun.
Single photon emission computed tomography (SPECT) in cerebellar diseasecerebello-cerebral diaschisis
Eur. Neurol.
Frontal dysfunction and frontal cortical synapse loss in alcoholism—the main cause of alcohol dementia?
Dement. Geriatr. Cogn. Disord.
Crossed cerebellar diaschisisoccurrence and resolution demonstrated with PET during carotid temporary balloon occlusion
Am. J. Neuroradiol.
PsyScopea new graphic interactive environment for designing psychology experiments
Behav. Res. Meth. Instruments Computers
Temporal dynamics of brain activation during a working memory task
Nature
Effects of Alcohol on the Nervous System of Man
Frontal dysfunction in neurologically normal chronic alcoholic subjectsmetabolic and neuropsychological findings
Psychol. Med.
Cerebellar involvement in cognitive functionevidence from neuroimaging
Int. Rev. Psychiatr.
Lobular patterns of cerebellar activation in verbal working memory and finger tapping tasks as revealed by functional MRI
J. Neurosci.
The neural basis of the central executive system of working memory
Nature
A positron emission tomography study of the short-term maintenance of verbal information
J. Neurosci.
Glutamate receptors in the frontal cortex of alcoholics
Alcohol Clin, Exp. Res.
Cited by (194)
Disruption of cerebellar-cortical functional connectivity predicts balance instability in alcohol use disorder
2022, Drug and Alcohol DependenceAddiction and the cerebellum with a focus on actions of opioid receptors
2021, Neuroscience and Biobehavioral ReviewsAlcohol: Neurobiology of Addiction
2021, Alcohol: Neurobiology of AddictionLocal and network-level dysregulation of error processing is associated with binge drinking
2021, NeuroImage: ClinicalAddictions NeuroImaging Assessment (ANIA): Towards an integrative framework for alcohol use disorder
2020, Neuroscience and Biobehavioral ReviewsHow the motor system integrates with working memory
2019, Neuroscience and Biobehavioral Reviews