Author: Alex Thompson

Alcohols Effects on the Brain: Neuroimaging Results in Humans and Animal Models PMC

Such studies suggest that EtOH alone, at least in the exposure protocols evaluated with MRI, does not result in the characteristics observed in human alcoholics. Conversely, rats exposed to vaporized EtOH during adolescence are reported to show persistent effects (i.e., ventricular enlargement and deficits in hippocampal volume) into adulthood (Ehlers et al. 2013; Gass et al. 2014). Mice exposed to EtOH during adolescence are similarly purported to exhibit long-lasting regional brain-volume deficits in the olfactory bulb and basal forebrain (Coleman et al. 2011, 2014). These results suggest that the adolescent rodent brain may be more vulnerable to enduring toxic effects of EtOH than the adult rodent brain. For instance, the protein tyrosine kinase (PTK) Fyn, through the phosphorylation of GluN2B in the dorsomedial striatum (DMS) of rodents, contributes to molecular and cellular neuroadaptations that drive goal-directed alcohol consumption [51,52].

1. In spectroscopy studies, it often is used as a reference for other peaks based on the incorrect assumption that its concentration is relatively constant (cf. Zahr et al. 2008, 2009, 2014b).
2. What researchers found 40 years ago is a likely reflection of the disorder seen today, but a mechanistic understanding of the full constellation of effects and the scope and limit of improvement with sobriety has evolved from being considered widespread and nonspecific to being specific in terms of brain circuitry and systems.
3. That is, older alcoholics exhibit reduced capacity for recovery compared with younger alcoholics (Fein et al. 1990; Munro et al. 2000; Reed et al. 1992; Rourke and Grant 1999).
4. Relationship between alcoholism, balance with and without use of stabilizing aids, and the cerebellar vermis.

Relative to findings in WKS, research demonstrates mild volume deficits in the mammillary bodies (Shear et al. 1996; Sullivan et al. 1999), hippocampi, and thalami in uncomplicated alcoholics compared with healthy controls (De Bellis et al. 2005; Chanraud et al. 2007; Pitel et al. 2012; Sullivan 2003; van Holst et al. 2012). That is, volume deficits are greatest in brains of subjects with KS (figure 5C) compared with brains of subjects with uncomplicated alcoholism (figure 5B) and brains unaffected by alcohol (figure 5A). Results suggest that mammillary-body damage is not prerequisite for the development of amnesia in alcoholism (Shear et al. 1996). MR findings also show hippocampal volume deficits in alcoholics compared with healthy controls (Agartz et al. 1999; Beresford et al. 2006; Kurth et al. 2004; Laakso et al. 2000; Sullivan et al. 1995; Wilhelm et al. 2008). Hippocampal volume deficits in alcoholism are influenced by age (Sullivan et al. 1995), even though age-related decline is difficult to detect in cross-sectional studies (Pfefferbaum et al. 2013; Raz et al. 2010; Sullivan et al. 2005b).

Thinning of the corpus callosum occurs in uncomplicated alcoholics and is more prominent in the anterior than posterior regions (Estruch et al. 1997; Pfefferbaum et al. 1996). As with WE and KS, evidence for MBD-like pathology in uncomplicated alcoholism raises the possibility that brain damage occurs on a continuum. The following section examines how brain structures and function respond when drinking stops. Total infratentorial volume (including pons, cerebellar hemispheres, vermis, fissures, cisterns, and fourth ventricle) is significantly smaller in uncomplicated alcoholics than control subjects.

Alcohol and the brain: from genes to circuits

ACD patients most frequently display ataxia, although other symptoms can include uncontrollable and repetitive eye movement (i.e., nystagmus) and speech problems resulting from impaired muscle control (i.e., dysarthria) (Fitzpatrick et al. 2012). Neuroimaging in ACD demonstrates damage disproportionately apparent in anterior superior portions of the cerebellar vermis (Sullivan et al. 2000a), with postmortem pathology indicating loss of cerebellar Purkinje cells (Feuerlein 1977). T1-weighted imaging in HE reveals bilateral, symmetrical, high-intensity signals in basal ganglia structures, particularly the globus pallidus and substantia nigra, probably due to manganese deposition and T1 shortening. T2-weighted fluid attenuation inversion recovery (FLAIR) shows hyperintense signals along the corticospinal tract and diffuse hyperintense white matter signal in the cerebral hemispheres. Since the early 1980s, conventional structural MRI has allowed researchers to visualize the living human brain. Detailed images of the brain are possible in part because the different brain tissue types (i.e., gray matter, white matter, and cerebrospinal fluid [CSF]) contain different proportions of water (Rumboldt et al. 2010).

Furthermore, researchers have hypothesized that the design, conduct, and analysis of a mainstay of animal experiments are questionable (Matthews 2008) and rarely undergo meta-analytical review for consensus (Mignini and Khan 2006; Peters et al. 2006; Pound et al. 2004; Sandercock and Roberts 2002). On a practical level, this depiction of memory abilities could mean that when provided with adequate aids, patients with KS may be able to enhance their otherwise fragile memory. Combined with evidence that alcoholic KS amnesia can range from mild to profound (Pitel et al. 2008), this possibility suggested that the brain substrate for amnesia could be different from another type of amnesia resistant to memory enhancement cueing (Milner 2005). The effects of alcohol on the brain vary depending on the dose and on individual factors, such as overall health. In general, the more alcohol a person drinks, the more likely it becomes that alcohol will damage the brain — both in the short and long term. Excessive alcohol consumption can have long-lasting effects on neurotransmitters in the brain, decreasing their effectiveness or even mimicking them.

An alcohol overdose occurs when there is so much alcohol in the bloodstream that areas of the brain controlling basic life-support functions—such as breathing, heart rate, and temperature control—begin to shut down. Symptoms of alcohol overdose include mental confusion, difficulty remaining conscious, vomiting, seizure, trouble breathing, slow heart rate, clammy skin, dulled responses (such as no gag reflex, which prevents choking), and extremely low body temperature. Mild swelling of astrocytes is proposed as the key event in the pathogenesis of HE (e.g., Takahashi et al. 1991).

One of the most consistent findings in alcohol-exposed rodents, ventricular enlargement, varies with timing and method of alcohol exposure. Even repeated binge exposures (i.e., 5 cycles of 4 days of intragastric binge EtOH exposure with 1 week abstinence in between), do not result in persistent effects on the brain detectable with MRI (Zahr et al. 2015). Although ventricular size increases with each binge EtOH exposure, there is rapid recovery during each week of abstinence (Zahr et al. 2015).

This is your brain on alcohol

This heterogeneity, and the complexity that it introduces, makes it difficult to thoroughly characterize the disorder. Animal models, in contrast to the indefinite natural course of alcohol use in humans, allow researchers to determine alcohol toxicity in a way that allows them to control for multiple genetic, environmental, and alcohol consumption factors. Animal models permit the study of underlying mechanisms, enabling researchers to better interpret findings from human studies. Acute and chronic use of alcohol affects the activity of multiple neuronal circuits, depicted here schematically in the context of a rodent brain. For example, alcohol activates the mesocorticolimbic brain reward circuit, which encompasses dopaminergic projections from the VTA in the midbrain to several forebrain structures including the striatum and cortex.

The rationale was that ethanol is such a small nondescript molecule that it is unlikely to have specific binding sites on proteins and is likely to nonspecifically enter the cell membranes and alter the physical properties of the lipids found in these membranes. Indeed, evidence emerged that ethanol could disorder brain membranes and that chronic alcohol treatment resulted in tolerance to this action (Chin and Goldstein 1977). This was an exciting development—a neurochemical action of alcohol that resulted in tolerance! However, rather large concentrations of alcohol were required to produce small changes in membrane structure. Moreover, it was difficult (perhaps impossible) to show a link between the lipid changes and changes in the functions of one or more proteins that could account for altered neuronal excitability.

Alcohol and the Brain: An Overview

One study estimated the incidence of CPM at 0.5 percent among the general population (Newell and Kleinschmidt-DeMasters 1996). However, prevalence is much higher (30 percent) among patients with liver transplants (Singh et al. 1994). For ACD prevalence, reports based on postmortem evaluation range from as low as 0.4 percent to as high as 42 percent of alcoholics (Riethdorf et al. 1991; Scholz et al. 1986; Stork 1967; Torvik and Torp 1986). Rates of ARD can depend on the setting, with facilities specializing in early identification and treatment of memory disorders reporting rates of 3 percent (McMurtray et al. 2006) and nursing homes reporting rates as high as 24 percent (Carlen et al. 1994; Oslin and Cary 2003; Ritchie and Villebrun 2008). Prevalence can also depend on the age of the population evaluated (i.e., higher prevalence of ARD is found in younger-onset [i.e., ages 45–64] dementia) (Draper et al. 2011b; Harvey et al. 2003). MBD appears to be very rare, with only about 250 cases reported between 1966 and 2001 (Helenius et al. 2001).

Studies of alcohol-related central nervous system disorders are used as a framework for findings in uncomplicated alcoholism. The article also examines studies of abstinence and relapse and current imaging studies of animal models of alcoholism and co-occurring brain disorders. The evidence suggests that human studies are necessary to identify and classify the brain systems modified by concomitants of alcoholism versus alcoholism, per se, and that animal models of alcoholism and its co-occurring brain disorders are essential for a mechanistic understanding of vulnerable brain systems. Another area requiring further research relates to individual differences in resilience and susceptibility to AUD.

Ventricular size in alcoholic and nonalcoholic humans and in alcohol-exposed and nonexposed rats. B) Early-generation computed tomography (CT)—the cerebrospinal fluid (CSF) in the large sulci shows up black. D) T1-weighted magnetic resonance (MR)—gray matter shows up gray, white matter is white, CSF is black. F) Regions showing activation on functional MR imaging (fMRI) (yellow) are superimposed on a T1-weighted MRI.

Analyses of individual components of DTI metrics have provided novel in vivo information about myelin integrity (measured as radial diffusivity) and axonal integrity (measured as axial diffusivity). In general, DTI findings in alcoholism indicate a greater role for demyelination than axonal degeneration in the compromise of white matter integrity. This distinction provides convergent validity with postmortem findings, establishing DTI metrics as in vivo markers of white matter neuropathology. Relationship between alcoholism, balance with and without use of stabilizing aids, and the cerebellar vermis.

Alcohol’s Effects on the Brain: Neuroimaging Results in Humans and Animal Models

Other studies detected morphological distortion of cell extensions (Harper et al. 1987; Pentney 1991) and volume reduction arising from shrinkage or deletion of cell bodies (Alling and Bostrom 1980; Badsberg-Jensen and Pakkenberg 1993; De la Monte 1988; Harper and Kril 1991, 1993; Lancaster 1993). Multiple classes of neuropeptide releasing neurons and neuropeptide receptors have been implicated as critical mediators of drinking behaviors, such as neurotensin [77], neuropeptide Y [78], oxytocin [79], opioid peptides [80,81] and corticotrophin-releasing factor (CRF). For instance, in rats and mice, chronic alcohol use alters the activity of the CeA through dysregulation of endocannabinoid, substance P, and corticotrophin releasing factor signaling [82–84]. The bed nucleus of the stria terminalis (BNST) also exhibits plasticity in endocannabinoids and CRF- expressing neurons due to chronic alcohol use, and these alterations modulate drinking, withdrawal-induced negative affect, and stress-induced alcohol seeking in mice [85,86]. Furthermore, the CeA and BNST regions are anatomically connected, and inhibition of CRF neurons projecting from the CeA to the BNST decreases escalation of alcohol intake and somatic withdrawal symptoms in rats [87]. The kinase mTOR in complex 1 (mTORC1) plays a crucial role in synaptic plasticity, learning and memory by orchestrating the translation of several dendritic proteins [39].

Such studies have demonstrated white-matter volume deficits as well as damage to selective gray-matter structures. Diffusion tensor imaging (DTI), by permitting microstructural characterization of white matter, has extended MRI findings in alcoholics. MR spectroscopy (MRS) allows quantification of several metabolites that shed light on brain biochemical alterations caused by alcoholism. This article focuses on MRI, DTI, and MRS findings in neurological disorders that commonly co-occur with alcoholism, including Wernicke’s encephalopathy, Korsakoff’s syndrome, and hepatic encephalopathy. Also reviewed are neuroimaging findings in animal models of alcoholism and related neurological disorders. This report also suggests that the dynamic course of alcoholism presents a unique opportunity to examine brain structural and functional repair and recovery.