Alcohol may compound its damaging effects through frontocerebellar circuitry

September 14, 2003

Patients with chronic alcoholism develop a wide range of brain structural and neuropsychological abnormalities. Deficits in executive functioning - such as problem solving, putting things in order, working memory, and doing multiple tasks at once - have been linked to lesions of the prefrontal cortex. Deficits in balance have been linked to lesions of the cerebellum. A study in the September issue of Alcoholism: Clinical & Experimental Research has found that the circuitry connecting these two spatially disparate brain regions, specifically through the pons and thalamus, may allow lesions to compound their effects on the prefrontal cortex and cerebellum.

"Neuropathological, neuroimaging, and neuropsychological studies have shown that the prefrontal cortex and regions of the cerebellum are especially vulnerable to the untoward effects of chronic alcoholism," said Edith Sullivan, a professor in the department of psychiatry and behavioral sciences at Stanford University School of Medicine and the sole author of the study. "Other neuroscience research provides evidence that, despite their geographical distance in the brain, the prefrontal cortex, which is at the frontal lobe, and the cerebellum, which is basically the hindbrain, are connected by far-reaching white matter tracts and a structural neural network. It seemed very likely that damage to one node or individual brain structure of this frontocerebellar system could affect other nodes within that circuitry, both structurally and functionally."

Sullivan chose to examine two major circuits of the frontocerebellar system, the pons and the thalamus. Information flows from the frontal cortex through the pons to the cerebellum; information also flows from the cerebellum through the thalamus to the frontal and parietal cortices.

Sullivan used magnetic resonance imaging (MRI) to derive regional brain measures from 25 nonamnesic alcoholic men. Control data were obtained from an age-matched group of 51 men. Previous results had revealed significant volume deficits among the alcoholics in the cerebellar hemispheres and vermis, pons, and thalamus as well as the prefrontal, frontal, and parietal cortex. These same individuals also demonstrated deficits in problem solving, visuospatial ability, and static postural stability. The purpose of this study was to closely examine associations among target brain volumes and neuropsychological deficits.

"We knew that various nodes that comprise the frontocerebellar networks show volume shrinkage in patients with chronic alcoholism," said Sullivan. "Such dysmorphology puts these individuals at risk of deficits in functions subserved by these brain structures. Given this background, we examined the relationship between brain volumes of the circuit nodes and observed that nodes that are known from animal studies to be highly connected also showed correlations in their volume measures."

"Pontine and thalamic volumes were not correlated with each other," Sullivan continued. "Pontine volumes correlated with white matter volumes of key regions of the cerebellum but not of the cortex. Thalamic volumes correlated with gray matter volumes of the cerebellum as well as certain regions of the cortex, including the parietal lobes, and inferior posterior vermian lobule, which itself correlated with parietal, prefrontal and frontal cortex volumes. These patterns of correlations were consistent with the separation of thalamic and pontine subcircuitry of the greater frontocerebellar circuit."

Sullivan also found correlations between observed brain volume deficits and specific functions.

"A volume deficit of the anterior vermis, but not the prefrontal or parietal cortex, was a unique predictor of balance scores," she said. "Volume deficits of the vermis and thalamus, but not the prefrontal cortex, were unique predictors of card-sorting scores, and a volume deficit of cerebellar hemispheric white matter, but not partietal cortex, was a predictor of visuospatial test performance."

The detection of relationships between brain structures and specific functions has been elusive in alcohol research, said Sullivan. "One reason may be that the approach to seeking them, that is, connecting one cortical brain locus with one behavior, was too simplified and too restricted to the cerebral cortex and excluded brain stem structures such as the pons and cerebellum."

Researchers know that two areas of neuropsychological functioning commonly compromised by chronic alcoholism are executive functions (such as problem solving, putting things in order, working memory, doing multiple tasks at once) and balance (the ability to walk a straight line or stand on one foot, especially with eyes closed or in the dark). Executive functions are typically disrupted by lesions of the prefrontal cortex, whereas balance and postural stability are disrupted by lesions of the cerebellum.

"The main idea expressed in this paper is that the compounded set of lesions may work together to disadvantage both types of functions," said Sullivan. "Indeed, in our previous research we have reported disproportionately greater deficits in executive and balance functions, compared with other components of function. A novelty of the current analysis is the observation that the extent of cerebellar volume shrinkage, which is related to the degree of balance problems, was also predictive of executive function deficits. Thus, it may be that the cerebellum, via brain circuitry, can exert a significant effect on functions of the prefrontal cortex."

Sullivan said she plans to challenge these initial findings with more tests of balance and sensorimotor integration, which typically require cerebellar functioning, and anticipatory responses, which typically require frontal lobe functioning, as well as more refined forms of brain imaging.
Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. This study was funded by the National Institute on Alcohol Abuse and Alcoholism.

Alcoholism: Clinical & Experimental Research

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