Trials In Tainted Space Alcohol Tolerance

• To estimate 1-year prevalence and correlates of alcohol abuse, dependence, and subthreshold dependence (diagnostic orphans) among middle-aged and elderly persons in the United States.2005-2007 National Surveys on Drug Use and Health.Sample included 10,015 respondents aged 50-64 years and 6,289 respondents older than 65 years.
• Phlogenzym® in Patients With Acute Thrombophlebitis - Efficacy and Tolerance The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.

Trials in tainted space. It's like CoC, but space sci-fi #98 to #93 - innateshelf. Reply +1 - m8 his profile picture is from the game #88 to #87 - innateshelf. Reply 0 - lmao #62 to #15 - timmity.

• 4Interactions
  • 4.3Sex
• 5Quests

Description

Large amazonian who can be found drinking at Anon’s Bar in Tavros Station. Her active hours are between 20:15 - 02:30.

Appearance

The seven foot, two-inch tall, brown-skinned, honey-haired obelisk of taut muscle and generous feminine curves that calls itself Ramis is a kaithrit, and is definitely one of the more generously sized examples of her race. Beneath her tight jeans, each of her big, brawny buttocks is the size of a basketball, and her dark tank top and sports bra do not disguise her wide, round D-cups. Ropy muscle trembles restlessly in her bare, washboard midriff and arms. Bursting out of the seat of her jeans are her twin tails, the same color as her pointed ears: tawny, with a paintbrush-like dappling of black.

In keeping with the rest of her, her eyes are a deep yellow. Her hair is pulled back into a ponytail, which combines with her high, proud cheekbones to give her a rather daunting profile at first glance; however, a full, expressive mouth that provides her with a huge, winning smile softens things considerably. Behind that, she has a voice and set of lungs that could be used to deafen people two planets away. She overall gives the impression of a boisterous late summer party looming ponderously into view.

History/Personality/Information of Note

Ramis is one of 28 different Ramises, the name given to all the members of her group they where differentiated by being given the first names of fruits and flowers. When she was just a kitten she was abandoned by her parents and put in an orphanage system sponsored by Snugglé on the Agricultural World of Newydd Casnewydd. At around the age of 16 the system stopped caring for her and put her to work paying off the debt she raised for raising her.

Wanting to escape this fate, she convinced one of her caretakers to take her to a space station and ditched them for a band of Pirates. After being fed some really potent alcohol she was treated as the ship’s 'Entertainment' which is what developed her Alcoholism and made her into a Size-Queen. Despite that, she did pick up a few tricks on in Mercenary skills and as soon as she was ready, ditches her old 'crew' and enlisted to be part of a bounty hunt that would instantly pay off her debt so Snugglé wouldn’t be able to legally send bounty hunters after her. Even after that, Snugglé often catches wind of her exploits and try to email her to come back as a security officer and even pay for her 'College Education'. But Ramis knows this will only create new debt.

Ramis is a boisterous and jolly individual who enjoys ragging on her mates and drinking a lot of drinks. She is picky about who she takes to bed, but she doesn’t shy away from having some adventures if she finds the person worthy. She has two main sexual pursuits: tall, muscular men who can dominate her and small, effeminate femboys whom she can tease and play with. Much to her chagrin, she most often finds herself dealing with either women or men who are her type but shirk from women who are stronger than them.

Interactions

Upon encounter, Ramis may invite or reject Captain Steele based on a number of factors.

If Steele is a female or hermaphrodite, Ramis will invite Steele to Drink with her (for 100 credits). If Steele does so, she will urge Steele on for more. Steele can choose to Keep Going (for 300 credits) or stop. Continuing will have Steele and Ramis drink until they are so intoxicated, they go on a hangover adventure. Whether or not Steele will remember this will depend on Steele’s alcohol tolerance.

If Steele is an effeminate male, Ramis will reject Steele the first time around and suggest Steele come back later. If Steele returns hours later (between 00:15 to 02:30), she will be raunchy for some trap sex. On repeat encounters, Ramis will hint at coming back later for some fun.

If Steele is a masculine male, Ramis will invite Steele to Drink (conditions and results similar to female encounter). Steele may also choose to Flirt with Ramis (if Steele is aroused enough). She will take that as an opportunity to challenge Steele in an arm wrestling match, where if Steele loses, Steele may have to drink a huge concoction of alcohol; though if Steele wins, Ramis will take Steele for a romp under the sheets.

If Steele returns and is a different form than the one she was previously introduce to, she will seemingly forget who Steele is and will reintroduce herself instead.

Post Recruitment

Ramis can be asked to sleep with the player regardless of sex. Waking up the next day will allow the player to Wake Her initiating bed sex or shower sex.

Switch ask Ramis to become switch from top to bottom or vice versa

• Ramis will only switch from top to bottom if the Steele has a penis of which the volume is greater than 5 cubic inches
• Must have done any crew sex scene at leas once

Sleep with

when sleeping with Ramis it is possible to wake her up leading to morning and shower sex. However, if the player doesn’t have morning shower sex with Ramis there is a chance that she will leave her panties in bed. The player will have the option to Take them or Leave them. If Ramis is still sleeping with you and you have stolen the panties, 48 hours later she will confront you on the matter as your preparing to go to bed. If the player lies to Ramis, she will become pissed, taking back her panties and refusing to sleep or have sex with you ever again. If the PC comes clean and is currently bottoming she will chastise you while playing with your cock and balls, leading to a light CBT one-off scene that increases lust to max and gives you blue balls. After punishing you, she let’s you keep her panties. If the PC is currently topping Ramis and comes clean, she’ll let you keep the panties, but only if you beat her in an Arm Wrestling match.

Tavros Nights

If you land on Tavros in the afternoon, Ramis will prepare to hit the town. Approach her to go with her. (From 13:00 to 18:30)

If you choose not to go with her she will temporarily become disabled and you will be unable to leave Tavros for about 8 hours until she returns. During which if the player is submissive to Ramis, has been pegged with a Hardlight strap-on, and their longest penis is less than 6 inches, she will give the an apology present in the form of the Silky Cock Bell.

If you do go with her you will first go to Anon’s Bar and become incredibly drunk, chewing ears and getting your ear chewed off by some of Ramis' old Mercenary friends. After an Arm Wrestling competition and stopping Ramis from doing something stupid, you head to a night club.

After dancing and more drinking you may encounter Ramis talking to another alien, at which point you can approach or leave. If you leave Ramis will meet up with you again and make you pick up her tab of 100 Credits. If you approach them you might be able to initiate group sex with Ramis and the alien(s). (See here)

Talk

Once onboard, Ramis can be asked about her past. She will only talk about it if you buy her a bottle of cheap scotch (100 credits). Her topics vary depending on how drunk she is.

When you get Ramis drunk on cheap Scotch after recruiting her the following talk options become available:

• Background - Ask where she came from.

Tainted Alcohol Deaths Us

• Adult Life - Ask how she got onto the Frontier.

• Mercing - She could surely tell you a few hair-raising tales.

• Hobbies - Which does she enjoy the most - clubbing, working out or doing boys?

With variations depending on how drunk she becomes.

Work out

It is possible to train with Ramis after recruiting her:

Strength II and stamina II can be accessed through the carry on branch of their respective workout.

Sex

Aside from the two party time sex scenes Ramis will only have sex with Steele if they are either a trap or masculine.

Bar Sex

Bar sex can only be accessed pre-recruitment.

Ramis has two particular interests in a sexual partner, each scene with some variation based on Steele’s anatomy and/or penis size:

Crew Sex

Crew sex can only be accessed post recruitment and require Steele to have either a masculine or trap appearance.

Ramis will automatically be either Top or bottom based on Steele’s appearance:

• Masculine Steele: Ramis is bottom.
• Trap Steele: Ramis is top.

Ramis can be asked to change from top to bottom and vice versa as long as Steele has a penis of which the volume is greater than 5 cubic inches

Ramis is Bottom

• Cats and Doggystyle - You fuck Ramis recklessly in the ship’s cockpit.
  • If Anno is a crewmember, she will walk in the first time this scene is played.
  • This may be followed up by Shower Sex

• Bench-Press Ride - Ramis tries to encourage you to go beyond your limit by teasing and riding your dick while you bench press.
  • Choosing Carry On during the strength work out whilst meeting all of the following conditions
    • Requires lust to be greater than 30
    • Requires Ramis to be bottom.
    • Requires non-tauric body.
    • Doesn’t look female to Ramis.

Ramis is top

• Ramis and the Wonderous Holodick - The player loans Ramis their Hardlight Strap-on so she can be the 'man'.
  • Requires a Hardlight strap-on in inventory.

• Corridor Molesting - Ramis catches you in the corridor and jerks you off while whispering dirty talk in your ear.

• Sit-Up Facesitting - Ramis tries to encourage you to go beyond your limit by teasing you and sitting on your face while you do sit-ups.
  • Choosing Carry On during the stamina work out whilst meeting all of the following conditions
    • Requires lust to be greater than 30
    • Requires Ramis to be top.
    • Requires non-tauric body.
    • Doesn’t look female to Ramis.

• Shower Sex - Who says cats don’t love water.
  • Variations for dominant and submissive Ramis.
  • Can be accessed through either of the following.
    • Choosing Ramis under sex in the shower menu.
    • Choosing to wake up Ramis when sleeping with her.

For all of the options during the morning after, Steele can choose to

• Sneak Out - No Snusnu.
• Wake Her Up and get a shower with her afterwards for your efforts.

• Lap Sit - Instead of doing that thing, your gonna sit on Ramis' lap while she toys with you.
  • Requires the PC’S height to be less than 6'4'
  • Requires a penis with the length of 6' or less.
  • Requires a penis wearing the Silky Cock Bell.
    • This scene has a 60% chance of occurring over the other scenes if they meet all the requirements.
    • This scene has 2 variations: If the player has Blue Balls they will get an orgasm. If not, Ramis will milk your cock without letting you experiencing an actual orgasm. Reduces cum stored to minimum and increases lust.

• Face Sitting - Ramis sits on your face while you lick out her pussy and ass and she plays with your willy.
  • Requires a penis.

• Lickjob - Ramis lifts you up and slowly laps at your cock.
  • Requires a penis wearing the Silky Cock Bell.
  • Requires the PC to have done the Face Sitting scene at least twice.

Tavros nights sex

• Trapaggedon - Ramis and the PC will have a foursome in which they two traps an Ausar pup named Kroy and his Saeri Faerie friend Vanesse.
  • Requires genitals.
  • Requires the PC to not be a trap.
  • Variations
    • Penis
      • Requires penis.
    • Vagina
      • Requires no penis.

• The Wandering Space Orc - Ramis and the PC will have a threesome in which they are dommed by a Thraggen Mercenary named Ohrskun.
  • Requires genitals.
  • Requires the player to not be a Man.
  • Variations for
    • Women
      • PC is a female.
    • Traps
      • PC is a trap.
      • Suck Balls - Worship those juicy, green orbs.
      • Fuck Him - See how much Mr. Macho here likes a taste of his own medicine.
        • Requires Libido to be greater than 70

Quests

Recruitment

Once Captain Steele has interacted with her once, she can be recruited as a Gunnery Officer for either 12,000 credits (if she doesn’t know you) or 10,000 credits (if you’ve either partied all night with her as a female or had sex with her as a male or trap).

Once on board, Ramis can be asked about her past. She will only talk about it if you buy her a bottle of cheap scotch (100 credits). Her topics vary depending on how drunk she is.

Alcoholism can affect the brain and behavior in a variety of ways, and multiple factors can influence these effects. A person’s susceptibility to alcoholism–related brain damage may be associated with his or her age, gender, drinking history, and nutrition, as well as with the vulnerability of specific brain regions. Investigators use a variety of methods to study alcoholism–related brain damage, including examining brains of deceased patients as well as neuroimaging, a technique that enables researchers to test and observe the living brain and to evaluate structural damage in the brain. Key words: neurobehavioral theory of AODU (alcohol and other drug use); alcoholic brain syndrome; brain atrophy; neuropsychological assessment; neurotransmission; risk factors; comorbidity; disease susceptibility; neuroimaging; treatment factors; survey of research

The brain, like most body organs, is vulnerable to injury from alcohol consumption. The risk of brain damage and related neurobehavioral deficits varies from person to person. This article reviews the many factors that influence this risk, the techniques used to study the effects of alcoholism¹ on the brain and behavior, and the implications of this research for treatment. (¹ Alcohol dependence, also known as alcoholism, is characterized by a craving for alcohol, possible physical dependence on alcohol, an inability to control one’s drinking on any given occasion, and an increasing tolerance to alcohol’s effects [American Psychiatric Association (APA) 1994].)

About half of the nearly 20 million alcoholics in the United States seem to be free of cognitive impairments. In the remaining half, however, neuropsychological difficulties can range from mild to severe. For example, up to 2 million alcoholics develop permanent and debilitating conditions that require lifetime custodial care (Rourke and Löberg 1996). Examples of such conditions include alcohol–induced persisting amnesic disorder (also called Wernicke–Korsakoff syndrome) and dementia, which seriously affects many mental functions in addition to memory (e.g., language, reasoning, and problem–solving abilities) (Rourke and Löberg 1996). Most alcoholics with neuropsychological impairments show at least some improvement in brain structure and functioning within a year of abstinence, but some people take much longer (Bates et al. 2002; Gansler et al. 2000; Sullivan et al. 2000). Unfortunately, little is known about the rate and extent to which people recover specific structural and functional processes after they stop drinking. However, research has helped define the various factors that influence a person’s risk for experiencing alcoholism–related brain deficits, as the following sections describe.

RISK FACTORS AND COMORBID CONDITIONS THAT INFLUENCE ALCOHOL–RELATED BRAIN DAMAGE

Alcoholism’s effects on the brain are diverse and are influenced by a wide range of variables (Parsons 1996). These include the amount of alcohol consumed, the age at which the person began drinking, and the duration of drinking; the patient’s age, level of education, gender, genetic background, and family history of alcoholism; and neuropsychiatric risk factors such as alcohol exposure before birth and general health status. Overall physical and mental health is an important factor because comorbid medical, neurological, and psychiatric conditions can interact to aggravate alcoholism’s effects on the brain and behavior. Examples of common comorbid conditions include:

• Medical conditions such as malnutrition and diseases of the liver and the cardiovascular system

• Neurological conditions such as head injury, inflammation of the brain (i.e., encephalopathy), and fetal alcohol syndrome (or fetal alcohol effects)

• Psychiatric conditions such as depression, anxiety, post–traumatic stress disorder, schizophrenia, and the use of other drugs (Petrakis et al. 2002).

These conditions also can contribute to further drinking.

MODELS FOR EXPLAINING ALCOHOL–RELATED BRAIN DAMAGE

Some of the previously mentioned factors that are thought to influence how alcoholism affects the brain and behavior have been developed into specific models or hypotheses to explain the variability in alcoholism–related brain deficits. The accompanying table lists the prevailing models (Oscar–Berman 2000). It should be noted that the models that focus on individual characteristics cannot be totally separated from models that emphasize affected brain systems because all of these factors are interrelated. Several of the models have been evaluated using specialized tests that enable researchers to make inferences about the type and extent of brain abnormalities.

*The right hemisphere is also believed to be more vulnerable to the effects of normal aging than the left hemisphere, which is taken as support for the premature aging hypothesis listed above.

NOTE: These hypotheses are not mutually exclusive; some are interrelated. Supporting data for these models come from neurobehavioral and electrophysiological studies, brain scans, and post mortem neuropathology.

Models Based on Characteristics of Individual Alcoholics

Premature Aging Hypothesis. According to this hypothesis, alcoholism accelerates natural chronological aging, beginning with the onset of problem drinking.

An alternate version suggests that older patients (age 50 and older) are especially susceptible to the cumulative effects of alcoholism, and aging is accelerated only later in life. The preponderance of scientific evidence suggests that although alcoholism–related brain changes may mimic some of the changes seen in older people, alcoholism does not cause premature aging. Rather, the effects of alcoholism are disproportionately expressed in older alcoholics (Oscar–Berman 2000).

Gender. Although it has been hypothesized that women’s brain functioning is more vulnerable to alcoholism than men’s, studies of gender differences have not consistently found this to be true (see Wuethrich 2001 for a review), even though women and men metabolize alcohol differently (i.e., women achieve higher blood alcohol contents [BACs] than men after consuming the same amount of alcohol). However, it is not known whether this comparison between men and women holds among older populations (Oscar–Berman 2000).

Family History. Family history of alcoholism has been found to be important because it can influence such things as tolerance for alcohol and the amount of consumption needed to feel alcohol’s effects. Also, studies examining brain functioning in people with and without a positive family history of alcoholism have shown that there are clear differences between the groups on measures of brain electrical activity (Porjesz and Begleiter 1998).

Vitamin Deficiency. Research on malnutrition, a common consequence of poor dietary habits in some alcoholics, indicates that thiamine deficiency (vitamin B₁) can contribute to damage deep within the brain, leading to severe cognitive deficits (Oscar–Berman 2000). The exact location of the affected parts of the brain and underlying neuropathological mechanisms are still being researched (see the next section).

Models Based on Vulnerable Brain Systems

The outer, convoluted layer of brain tissue, called the cerebral cortex or the gray matter, controls most complex mental activities (see figure 1). Just beneath it are the nerve fibers, called the white matter, that connect different cortical regions and link cortical cells with other structures deep inside the brain (subcortical regions).

Areas of the brain that are especially vulnerable to alcoholism–related damage are the cerebral cortex and subcortical areas such as the limbic system (important for feeling and expressing emotions), the thalamus (important for communication within the brain), the hypothalamus (which releases hormones in response to stress and other stimuli and is involved in basic behavioral and physiological functions), and the basal forebrain (the lower area of the front part of the brain, involved in learning and memory) (Oscar–Berman 2000). Another brain structure that has recently been implicated is the cerebellum (Sullivan 2000), situated at the base of the brain, which plays a role in posture and motor coordination and in learning simple tasks.

Alcohol–Related Brain Atrophy. According to one hypothesis, shrinkage (i.e., atrophy) of the cerebral cortex and white matter, as well as possible atrophy of basal forebrain regions, may result from the neurotoxic effects of alcohol (Lishman 1990). Furthermore, thiamine deficiency may result in damage to portions of the hypothalamus (perhaps because blood vessels break in that region). According to this hypothesis, alcoholics who are susceptible to alcohol toxicity² may develop permanent or transient cognitive deficits associated with brain shrinkage. (² Some people may have better immunity than others to alcohol’s toxic effects.) Those who are susceptible to thiamine deficiency will develop a mild or transient amnesic disorder, with short–term memory loss as the salient feature. Patients with dual vulnerability, those with a combination of alcohol neurotoxicity and thiamine deficiency, will have widespread damage to large regions of the brain, including structures deep within the brain such as the limbic system. These people will exhibit severe short–term memory loss and collateral cognitive impairments (Oscar–Berman 2000).

Frontal Lobe Vulnerability. Although alcoholics have diffuse damage in the cerebral cortex of both hemispheres of the brain, neuropathological studies performed on the brains of deceased patients as well as findings derived from neuroimaging studies of living brains point to increased susceptibility of frontal brain systems to alcoholism–related damage (Moselhy et al. 2001; Oscar–Berman 2000; Sullivan 2000). The frontal lobes are connected with all other lobes of the brain (i.e., the parietal, temporal, and occipital lobes on both halves of the brain; see figure 1), and they receive and send fibers to numerous subcortical structures. Behavioral neuroscientists have determined that the anterior region of the frontal lobes (i.e., the prefrontal cortex) is important for engaging in ordinary cognitive, emotional, and interpersonal activities. The prefrontal cortex is considered the brain’s executive—that is, it is necessary for planning and regulating behavior, inhibiting the occurrence of unnecessary or unwanted behaviors, and supporting adaptive “executive control” skills such as goal–directed behaviors, good judgment, and problem–solving abilities. Disruptions of the normal inhibitory functions of prefrontal networks often have the interesting effect of releasing previously inhibited behaviors. As a result, a person may behave impulsively and inappropriately, which may contribute to excessive drinking.

There is evidence that the frontal lobes are particularly vulnerable to alcoholism–related damage, and the brain changes in these areas are most prominent as alcoholics age (Oscar–Berman 2000; Pfefferbaum et al. 1997; Sullivan 2000) (see figure 2). Other studies of frontal lobe function in older alcoholics have confirmed reports of a correlation between impaired neuropsychological performance (e.g., executive control skills, as noted above) and decreased blood flow or metabolism (energy use) in the frontal lobes, as seen using neuroimaging techniques (Adams et al. 1998).

Vulnerability of the Right Hemisphere. Some investigators have hypothesized that functions controlled by the brain’s right hemisphere are more vulnerable to alcoholism–related damage than those carried out by the left hemisphere (see Oscar–Berman and Schendan 2000 for review). Each hemisphere of the human brain is important for mediating different functions. The left hemisphere has a dominant role in communication and in understanding the spoken and written word. The right hemisphere is mainly involved in coordinating interactions with the three–dimensional world (e.g., spatial cognition).

Differences between the two cerebral hemispheres can easily be seen in patients with damage to one hemisphere but not the other (from stroke, trauma, or tumor). Patients with left hemispheric damage often have problems with language; patients with right hemispheric damage often have difficulty with maps, designs, music, and other nonlinguistic materials, and they may show emotional apathy.

Alcoholics may seem emotionally “flat” (i.e., they are less reactive to emotionally charged situations), and may have difficulty with the same kinds of tasks that patients with damage to the right hemisphere have difficulty with. New research has shown that alcoholics are impaired in emotional processing, such as interpreting nonverbal emotional cues and recognizing facial expressions of emotion (Kornreich et al. 2002; Monnot et al. 2002; Oscar–Berman 2000). Yet, despite the fact that emotional functioning can be similar in some alcoholics and people with right hemisphere damage, research provides only equivocal support for the hypothesis that alcoholism affects the functioning of the right hemisphere more than the left (Oscar–Berman and Schendan 2000). Impairments in emotional functioning that affect alcoholics may reflect abnormalities in other brain regions which also influence emotional processing, such as the limbic system and the frontal lobes.

Disruption of Neurotransmitter Systems. Brain cells (i.e., neurons) communicate using specific chemicals called neurotransmitters. Neuronal communication takes place at the synapse, where cells make contact. Specialized synaptic receptors on the surface of neurons are sensitive to specific neurotransmitters. Alcohol can change the activity of neurotransmitters and cause neurons to respond (excitation) or to interfere with responding (inhibition) (Weiss and Porrino 2002), and different amounts of alcohol can affect the functioning of different neurotransmitters. Over periods of days and weeks, receptors adjust to chemical and environmental circumstances, such as the changes that occur with chronic alcohol consumption, and imbalances in the action of neurotransmitters can result in seizures, sedation, depression, agitation, and other mood and behavior disorders.

The major excitatory neurotransmitter in the human brain is the amino acid glutamate. Small amounts of alcohol have been shown to interfere with glutamate action. This interference could affect several brain functions, including memory, and it may account for the short–lived condition referred to as “alcoholic blackout.” Chronic alcohol consumption increases glutamate receptor sites in the hippocampus, an area in the limbic system that is crucial to memory and often involved in epileptic seizures. During alcohol withdrawal, glutamate receptors that have adapted to the long–term presence of alcohol may become overactive, and this overactivity has been repeatedly linked to neuronal death, which is manifested by conditions such as stroke and seizures. Deficiencies of thiamine caused by malnutrition may contribute to this potentially destructive overactivity (Crews 2000).

Gamma–aminobutyric acid (GABA) is the major inhibitory neurotransmitter. Available evidence suggests that alcohol³ initially potentiates GABA’s effects (i.e., it increases inhibition, and often the brain becomes mildly sedated). (³ The amount of alcohol needed to cause this effect depends on the person.) However, over time, prolonged, excessive alcohol consumption reduces the number of GABA receptors. When the person stops drinking, decreased inhibition combined with a deficiency of GABA receptors may contribute to overexcitation throughout the brain. This in turn can contribute to withdrawal seizures within a day or two. It should be noted that the balance between the inhibitory action of GABA and the excitatory action of glutamate is a major determinant of the level of activity in certain regions of the brain; the effects of GABA and glutamate on withdrawal and brain function are probably interactive (see Valenzuela 1997 for review).

Alcohol directly stimulates release of the neurotransmitter serotonin, which is important in emotional expression, and of the endorphins, natural substances related to opioids, which may contribute to the “high” of intoxication and the craving to drink. Alcohol also leads to increases in the release of dopamine (DA), a neurotransmitter that plays a role in motivation and in the rewarding effects of alcohol (Weiss and Porrino 2002). Changes in other neurotransmitters such as acetylcholine have been less consistently defined. Future research should help to clarify the importance of many neurochemical effects of alcohol consumption. Furthermore, areas amenable to pharmacological treatment could be identified by studying regionally specific brain neurochemistry in vivo using neuroimaging methods such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT) (described below). New information from neuroimaging studies could link cellular changes directly to brain consequences observed clinically. In the absence of a cure for alcoholism, a detailed understanding of the actions of alcohol on nerve cells may help in designing effective therapies.

TECHNIQUES FOR STUDYING ALCOHOL–RELATED BRAIN DAMAGE

Researchers use multiple methods to understand the etiologies and mechanisms of brain damage across subgroups of alcoholics. Behavioral neuroscience offers excellent techniques for sensitively assessing distinct cognitive and emotional functions—for example, the measures of brain laterality (e.g., spatial cognition) and frontal system integrity (e.g., executive control skills) mentioned earlier. Followup post mortem examinations of brains of well–studied alcoholic patients offer clues about the locus and extent of pathology and about neurotransmitter abnormalities. Neuroimaging techniques provide a window on the active brain and a glimpse at regions with structural damage.

Behavioral Neuroscience

Behavioral neuroscience studies the relationship between the brain and its functions—for example, how the brain controls executive functions and spatial cognition in healthy people, and how diseases like alcoholism can alter the normal course of events. This is accomplished by using specialized tests designed expressly to measure the functions of interest. Among the tests used by scientists to determine the effects of alcoholism on executive functions controlled by the frontal lobes are those that measure problem–solving abilities, reasoning, and the ability to inhibit responses that are irrelevant or inappropriate (Moselhy et al. 2001; Oscar–Berman 2000). Tests to measure spatial cognition controlled by the right hemisphere include those that measure skills important for recognizing faces, as well as those that rely on skills required for reading maps and negotiating two– and three–dimensional space (visuospatial tasks) (Oscar–Berman and Schendan 2000). With the advent of sophisticated neuroimaging techniques (described below), scientists can even observe the brain while people perform many tasks sensitive to the workings of certain areas of the brain.

Neuropathology

Researchers have gained important insights into the anatomical effects of long–term alcohol use from studying the brains of deceased alcoholic patients. These studies have documented alcoholism–related atrophy throughout the brain and particularly in the frontal lobes (Harper 1998). Post mortem studies will continue to help researchers understand the basic mechanisms of alcohol–induced brain damage and regionally specific effects of alcohol at the cellular level.

Neuroimaging

Remarkable developments in neuroimaging techniques have made it possible to study anatomical, functional, and biochemical changes in the brain that are caused by chronic alcohol use. Because of their precision and versatility, these techniques are invaluable for studying the extent and the dynamics of brain damage induced by heavy drinking. Because a patient’s brain can be scanned on repeated occasions, clinicians and researchers are able to track a person’s improvement with abstinence and deterioration with continued abuse. Furthermore, brain changes can be correlated with neuropsychological and behavioral measures taken at the same time. Brain imaging can aid in identifying factors unique to the individual which affect that person’s susceptibility to the effects of heavy drinking and risk for developing dependence, as well as factors that contribute to treatment efficacy.

Imaging of Brain Structure. With neuroimaging techniques such as computerized tomography (CT) and magnetic resonance imaging (MRI), which allow brain structures to be viewed inside the skull, researchers can study brain anatomy in living patients. CT scans rely on x–ray beams passing through different types of tissue in the body at different angles. Pictures of the “inner structure” of the brain are based on computerized reconstruction of the paths and relative strength of the x–ray beams. CT scans of alcoholics have revealed diffuse atrophy of brain tissue, with the frontal lobes showing the earliest and most extensive shrinkage (Cala and Mastaglia 1981).

MRI techniques have greatly influenced the field of brain imaging because they allow noninvasive measurement of both the anatomy (using structural MRI) and the functioning (using functional magnetic resonance imaging [fMRI], described below) of the brain with great precision. Structural MRI scans are based on the observation that the protons derived from hydrogen atoms, which are richly represented in the body because of its high water content, can be aligned by a magnetic field like small compass needles. When pulses are emitted at a particular frequency, the protons briefly switch their alignment and “relax” back into their original state at slightly different times in different types of tissue. The signals they emit are detected by the scanner and converted into highly precise images of the tissue. MRI methods have confirmed and extended findings from post mortem and CT scan studies—namely, that chronic use of alcohol results in brain shrinkage. This shrinkage is most marked in the frontal regions and especially in older alcoholics (Oscar–Berman 2000; Pfefferbaum et al. 1997; Sullivan 2000). Other brain regions, including portions of the limbic system and the cerebellum, also are vulnerable to shrinkage.

Imaging of Brain Function: Hemodynamic Methods. Hemodynamic methods create images by tracking changes in blood flow, blood volume, blood oxygenation, and energy metabolism that occur in the brain in response to neural activity. PET and SPECT are used to map increased energy consumption by the specific brain regions that are engaged as a patient performs a task. One example of this mapping involves glucose, the main energy source for the brain. When a dose of a radioactively labeled glucose (a form of glucose that is absorbed normally but cannot be fully metabolized, thus remaining “trapped” in a cell) is injected into the bloodstream of a patient performing a memory task, those brain areas that accumulate more glucose will be implicated in memory functions. Indeed, PET and SPECT studies have confirmed and extended earlier findings that the prefrontal regions are particularly susceptible to decreased metabolism in alcoholic patients (Berglund 1981; Gilman et al. 1990). It is important to keep in mind, however, that frontal brain systems are connected to other regions of the brain, and frontal abnormalities may therefore reflect pathology elsewhere (Moselhy et al. 2001).

Even though using low doses of radioactive substances that decay quickly minimizes the risks of radiation exposure, newer and safer methods have emerged, such as MRI methods. MRI is noninvasive, involves no radioactive risks, and provides both anatomical and functional information with high precision. The fMRI method is sensitive to metabolic changes in the parts of the brain that are activated during a particular task. A local increase in metabolic rate results in an increased delivery of blood and increased oxygenation of the region participating in a task. The blood oxygenation level–dependent (BOLD) effect is the basis of the fMRI signal. Like PET and SPECT, fMRI permits observing the brain “in action,” as a person performs cognitive tasks or experiences emotions.

In addition to obtaining structural and functional information about the brain, MRI methodology has been used for other specialized investigations of the effects of alcohol on the brain. For example, structural MRI can clearly delineate gray matter from white matter but cannot detect damage to individual nerve fibers forming the white matter. By tracking the diffusion of water molecules along neuronal fibers, an MRI technique known as diffusion tensor imaging (DTI) can provide information about orientations and integrity of nerve pathways, confirming earlier findings from post mortem studies which suggested that heavy drinking disrupts the microstructure of nerve fibers. Moreover, the findings correlate with behavioral tests of attention and memory (Pfefferbaum et al. 2000). These nerve pathways are critically important because thoughts and goal–oriented behavior depend on the concerted activity of many brain areas.

Another type of MRI application, magnetic resonance spectroscopy imaging (MRSI), provides information about the neurochemistry of the living brain. MRSI can evaluate neuronal health and degeneration and can detect the presence and distribution of alcohol, certain metabolites, and neurotransmitters.

Imaging of Brain Function: Electromagnetic Methods. In spite of their excellent spatial resolution—that is, the ability to show precisely where the activation changes are occurring in the brain—hemodynamic methods such as PET, SPECT, and fMRI have limitations in showing the time sequence of these changes. Activation maps can reveal brain areas involved in a particular task, but they cannot show exactly when these areas made their respective contributions. This is because they measure hemodynamic changes (blood flow and oxygenation), indicating the neuronal activation only indirectly and with a lag of more than a second. Yet, it is important to understand the order and timing of thoughts, feelings, and behaviors, as well as the contributions of different brain areas.

The only methods capable of online detection of the electrical currents in neuronal activity are electromagnetic methods such electroencephalography (EEG), event–related brain potentials (ERP),⁴ and magnetoencephalography (MEG). (⁴ The ERP method is considered derived from electroencephalography.) EEG reflects electrical activity measured by small electrodes attached to the scalp. Event–related potentials are obtained by averaging EEG voltage changes that are time–locked to the presentation of a stimulus such as a tone, image, or word. MEG uses sensors in a machine that resembles a large hair dryer to measure magnetic fields generated by brain electrical activity. These techniques are harmless and give us insight into the dynamic moment–to–moment changes in electrical activity of the brain. They show when the critical changes are occurring, but their spatial resolution is ambiguous and limited.

ERP and MEG have confirmed that alcohol exerts deleterious effects on multiple levels of the nervous system. These effects include impairment of the lower–level brain stem functions resulting in behavioral symptoms such as dizziness, involuntary eye movement (i.e., nystagmus), and insecure gait, as well as impairment of higher order functioning such as problem solving, memory, and emotion. ERP and MEG are remarkably sensitive to many alcohol–related phenomena and can detect changes in the brain that are associated with alcoholism, withdrawal, and abstinence. That is, these methods show different activity patterns between healthy and alcohol–dependent individuals, those in withdrawal, and those with a positive family history of alcoholism. As shown in figure 3, when brain electrical activity is measured in response to target stimuli (which require the subject to respond in some way) and nontarget stimuli (to be ignored by the subject), the brains of alcoholics are less responsive than the brains of nonalcoholic control subjects. Some of the ERP abnormalities observed in alcoholics do not change with abstinence, and similar abnormalities have been reported in patients who do not drink but come from families with a history of alcoholism. The possibility that such abnormalities may be genetic markers for the predisposition for alcoholism is under intensive scrutiny in studies combining genetic and electromagnetic measures in people with or without a family history of alcoholism (Porjesz and Begleiter 1998).

IMPLICATIONS FOR TREATMENT

Because alcoholism is associated with diverse changes to the brain and behavior, clinicians must consider a variety of treatment methods to promote cessation of drinking and recovery of impaired functioning. With an optimal combination of neuropsychological observations and structural and functional brain imaging results, treatment professionals may be able to develop a number of predictors of abstinence and relapse outcomes, with the purpose of tailoring treatment methods to each individual patient. Neuroimaging methods have already provided significant insight into the nature of brain damage caused by heavy alcohol use, and the integration of results from different methods of neuroimaging will spur further advances in the diagnosis and treatment of alcoholism–related damage. Clinicians also can use brain imaging techniques to monitor the course of treatment because these techniques can reveal structural, functional, and biochemical changes in living patients across time as a result of abstinence, therapeutic interventions, withdrawal, or relapse. For example, functional imaging studies might be used to evaluate the effectiveness of drugs such as naltrexone on withdrawal–induced craving. (Naltrexone is an anticraving medicine that suppresses GABA activity.) Additionally, neuroimaging research already has shown that abstinence of less than a month can result in an increase in cerebral metabolism, particularly in the frontal lobes, and that continued abstinence can lead to at least partial reversal in loss of brain tissue (Sullivan 2000). Neuroimaging indicators also can be useful in prognosis, permitting identification and timely treatment of patients at high risk for relapse.

SUMMARY

Alcoholics are not all alike; they experience different subsets of symptoms, and the disease has different origins for different people. Therefore, to understand the effects of alcoholism, it is important to consider the influence of a wide range of variables. Researchers have not yet found conclusive evidence for the idea that any one variable can consistently and completely account for the brain deficits found in alcoholics. The most plausible conclusion is that neurobehavioral deficits in some alcoholics result from the combination of prolonged ingestion of alcohol, which impairs the way the brain normally works, and individual vulnerability to some forms of brain damage. Characterizing what makes alcoholics “vulnerable” remains the subject of active research.

In the search for answers, it is necessary to use as many kinds of tools as possible, keeping in mind that specific deficits may be observed only with certain methods, specific paradigms, and particular types of people with distinct risk factors. Neuroscience provides sensitive techniques for assessing changes in mental abilities and observing brain structure and function over time. When techniques are combined, it will be possible to identify the pattern, timing, and distribution of the brain regions and behaviors most affected by alcohol use and abuse. Electromagnetic methods (ERP and MEG) specify the timing of alcohol–induced abnormalities, but the underlying neural substrate (i.e., the anatomical distribution of the participating brain areas) cannot be unequivocally evaluated based on these methods alone. Conversely, the hemodynamic methods (fMRI, PET, and SPECT) have good spatial resolution but offer little information about the sequence of events. Drawing on the respective advantages of these complementary methods, an integrated multimodal approach can reveal where in the brain the critical changes are occurring, as well as the timing and sequence in which they happen (Dale and Halgren 2001). Such confluence of information can provide evidence linking structural damage, functional alterations, and the specific behavioral and neuropsychological effects of alcoholism. These measures also can determine the degree to which abstinence and treatment result in the reversal of atrophy and dysfunction.

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