Elsevier

NeuroImage

Volume 19, Issue 4, August 2003, Pages 1510-1520
NeuroImage

Regular article
Increased frontocerebellar activation in alcoholics during verbal working memory: an fMRI study

https://doi.org/10.1016/S1053-8119(03)00102-2Get rights and content

Abstract

Although there is clear evidence of alcoholism-related damage to the frontal lobes and cerebellum from neuroimaging, neuropathological, and neuropsychological studies, the functional role of the cerebellum and cerebrocerebellar circuits related to verbal working memory deficits of alcoholics have not been well studied. Alcoholic and nonalcoholic subjects performed a Sternberg verbal working memory task while receiving an fMRI scan in a 3T magnet. This task has been found in previous studies to reliably activate the articulatory control and phonological storage components of the phonological loop (left frontal, left temporal/parietal structures, right superior cerebellar regions) in young healthy controls. We hypothesized that the alcoholics would show a different pattern of activation from the controls, based on the regions of interest (ROIs) identified from a previous study of healthy subjects. Behavioral results showed the alcoholics to be performing at a comparable level to the matched controls in terms of accuracy and median reaction time, with no statistically significant differences. However, analysis of the functional data revealed that the alcoholics exhibited greater activation in the left frontal (BA44/45) and right superior cerebellum (HVI) regions relative to the matched controls. These findings suggest that brain activation in left frontal and right cerebellar regions that support the articulatory control system of verbal working memory may require a compensatory increase in alcoholics in order to maintain the same level of performance as controls.

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)

  • E.H. Schumacher et al.

    PET evidence for an amodal verbal working memory system

    Neuroimage

    (1996)
  • E.E. Smith et al.

    Working memorya view from neuroimaging

    Cogn. Psychol.

    (1997)
  • A. Torvik et al.

    The prevalence of alcoholic cerebellar atrophya morphometric and histological study of an autopsy material

    J. Neurol. Sci.

    (1986)
  • D. Wildgruber et al.

    Differential contributions of motor cortex, basal ganglia, and cerebellum to speech motor controleffects of syllable repetition rate evaluated by fMRI

    Neuroimage

    (2001)
  • K.M. Adams et al.

    Neuropsychological deficits are correlated with frontal hypometabolism in positron emission tomography studies of older alcoholic patients

    Alcohol Clin. Exp. Res.

    (1993)
  • N.C. Andreasen et al.

    Short-term and long-term verbal memorya positron emission tomography study

    Proc. Natl. Acad. Sci. USA

    (1995)
  • E. Awh et al.

    Dissociation of storage and rehearsal in verbal working memoryevidence from positron emission tomography

    Psychol. Sci.

    (1996)
  • S. Boni et al.

    Crossed cerebello-cerebral diaschisisa SPECT study

    Nucl. Med. Commun.

    (1992)
  • M.I. Botez et al.

    Single photon emission computed tomography (SPECT) in cerebellar diseasecerebello-cerebral diaschisis

    Eur. Neurol.

    (1991)
  • A. Brun et al.

    Frontal dysfunction and frontal cortical synapse loss in alcoholism—the main cause of alcohol dementia?

    Dement. Geriatr. Cogn. Disord.

    (2001)
  • J.A. Brunberg et al.

    Crossed cerebellar diaschisisoccurrence and resolution demonstrated with PET during carotid temporary balloon occlusion

    Am. J. Neuroradiol.

    (1992)
  • Chen, S.A., Pryor, M.R., Desmond, J.E., 2002. Cerebellar involvement in encoding, maintenance, and retrieval components...
  • J.D. Cohen et al.

    PsyScopea new graphic interactive environment for designing psychology experiments

    Behav. Res. Meth. Instruments Computers

    (1993)
  • J.D. Cohen et al.

    Temporal dynamics of brain activation during a working memory task

    Nature

    (1997)
  • Corkin, S., Growdon, J.H., Sullivan, E.V., Nissen, M.J., Huff, F.J., 1986. Assessing treatment effects from a...
  • C.B. Courville

    Effects of Alcohol on the Nervous System of Man

    (1955)
  • M.H. Dao-Castellana et al.

    Frontal dysfunction in neurologically normal chronic alcoholic subjectsmetabolic and neuropsychological findings

    Psychol. Med.

    (1998)
  • J.E. Desmond

    Cerebellar involvement in cognitive functionevidence from neuroimaging

    Int. Rev. Psychiatr.

    (2001)
  • Desmond, J.E., 2001b. Cerebro-cerebellar interactions in articulatory loops with and without working memory: an fMRI...
  • J.E. Desmond et al.

    Lobular patterns of cerebellar activation in verbal working memory and finger tapping tasks as revealed by functional MRI

    J. Neurosci.

    (1997)
  • M. D’Esposito et al.

    The neural basis of the central executive system of working memory

    Nature

    (1995)
  • J.A. Fiez et al.

    A positron emission tomography study of the short-term maintenance of verbal information

    J. Neurosci.

    (1996)
  • G. Freund et al.

    Glutamate receptors in the frontal cortex of alcoholics

    Alcohol Clin, Exp. Res.

    (1996)
  • Cited by (194)

    • Alcohol: Neurobiology of Addiction

      2021, Alcohol: Neurobiology of Addiction
    • How the motor system integrates with working memory

      2019, Neuroscience and Biobehavioral Reviews
    View all citing articles on Scopus
    View full text