Novel imaging technique reveals how alcohol addiction and abstinence alter the functional architecture of the brain


Employing advanced technologies that allow whole brain imaging at single-cell resolution, researchers at University of California San Diego School of Medicine report that in an alcohol-dependent mouse model, the rodent brain’s functional architecture is substantially remodeled.

But when deprived of alcohol, the mice displayed increased coordinated brain activity and reduced modularity compared to nondrinker or casual drinker mice.

The findings, published in the January 14, 2020 online issue of PNAS, also identified several previously unsuspected regions of the brain relevant to alcohol consumption, providing new research targets for better understanding and treatment of alcohol dependence in humans.

“The neuroscience of addiction has made tremendous progress, but the focus has always been on a limited number of brain circuits and neurotransmitters, primarily dopaminergic neurons, the amygdala and the prefrontal cortex,” said senior author Olivier George, PhD, associate professor in the Department of Psychiatry at UC San Diego School of Medicine.

“Research groups have been fighting for years about whether ‘their’ brain circuit is the key to addiction. Our results confirm these regions are important, but the fact that we see such a massive remodeling of the functional brain architecture was a real shock.

It’s like studying the solar system and then discovering that there is an entire universe behind it.

It shows that if you really want to understand the neurobiological mechanisms leading to addiction, you can’t just look at a handful of brain regions, you need to look at the entire brain, you need to take a step back and consider the whole organ.”

George said the findings further undermine the idea that addiction is simply a psychological condition or consequence of lifestyle. “You would be surprised at how prevalent this view remains,” he said. “The brain-wide remodeling of the functional architecture observed here is not ‘normal.’

It is not observed in a naïve animal. It is not observed in an animal that drinks recreationally. It is only observed in animals with a history of alcohol dependence and it is massive.

Such a decrease in brain modularity has been observed in numerous brain disorders, including Alzheimer’s disease, traumatic brain injury and seizure disorders.”

Brain modularity is the theory that there are functionally specialized regions in the brain responsible for different, specific cognitive processes. For example, the frontal lobes of the human brain are involved in executive functions, such as reasoning and planning, while the fusiform face area located in the lower rear of the brain is involved in recognizing faces.

Reduced modularity, said George, likely interferes with “normal neuronal activity and information processing and contributes to cognitive impairment, emotional distress and intense craving observed in mice during abstinence from alcohol.”

This shows the generated brain atlas

Artistic representation of changes in mouse brain networks with alcohol dependence. The left side represents control individuals with numerous networks and small sets of connected brain regions indicated by lines.

The right side represents individual mice with a history of alcohol dependence, depicting a small set of only three brain networks with a high number of connections. Image is credited to UC San Diego Health Sciences.

Due to the format of the testing, George said it was not clear if the reduced modularity was permanent. “So far, we only know that it lasts at least one week into abstinence. We have not tested longer durations of abstinence, but it’s one of our goals.”

George and colleagues used multiple new and emerging imaging technologies to create their whole-brain atlas of mouse brains, capable of being viewed at the level of single cells. The result was a first, they said, providing unprecedented data and insights.

“This new approach allows us to explore an entirely new universe. It can answer so many questions. What I am most interested in now is figuring out how early these brain changes start and how long do they last for.

This would be critical to understanding when the switch to addiction happens and when does your brain come back to normal, if it ever does. We are also very interested in comparing the brain network of alcohol dependence with other drugs, such as cocaine, nicotine and methamphetamines.”

The imaging approach cannot yet be used with human brains, which are far larger and more complex. “I don’t think that it is possible to do it in humans now, the technology is just not there,” said George.

“But when I started doing this research 15 years ago, this technique didn’t exist at all and I never ever imagined it would be possible, so who knows what the future will bring.”

Co-authors include: Adam Kimbrough, UC San Diego; Daniel J. Lurie and Mark D’Esposito, UC Berkeley; Andres Collazo, California Institute of Technology; and Max Kreifeldt, Harpreet Sidhu, Giovana Camila Macedo and Candice Contet, The Scripps Research Institute.

Disclosure: Olivier George’s spouse is owner of Simply-Lab, LLC and has equity interest.

Drug/Substance Abuse

Drugs abuse refers to the excessive use of drugs that tends to activate brain reward system that reinforces behaviors and the production of memories. Substance abuse has been adopted by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) to include 10 separate classes of drugs, including alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics and anxiolytics, stimulants, tobacco and other substances. These drugs produce such an intense activation of the reward system that normal activities may be neglected. Instead of achieving reward through adaptive behaviors, drugs of abuse directly activate the reward pathways.

Each class of drug produces different pharmacological mechanisms, but the drugs typically activate the system and produce a feeling of pleasure, often referred to as a high.Substance-induced disorders include intoxication, withdrawal and substance-induced mental disorders such as psychotic disorders, bipolar disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder, sleep disorders, sexual dysfunction, delirium, and neurocognitive disorders.

Alcohol Abuse

Alcohol abuse refers to drinking too much alcohol on occasion, as well as habits of drinking alcohol that result in harm to health, ability to work behavior, and judgment. Alcohol abusers generally are not dependent on alcohol. Alcohol dependence, on the other hand, means a person needs alcohol to get through his or her day. Alcohol abuse and alcohol dependency were previous terms used in DSM-IV. DSM-5 has combined alcohol abuse and alcohol dependence to create a unified disorder, alcohol use disorder (AUD).[1][2][3]


Drug/Substance Abuse

Family Risk Factors

  • Parental drug/alcohol use
  • Intrauterine exposure to drugs
  • Marital conflict
  • family dysfunction
  • Use among siblings
  • Recent trauma
  • Parent-child conflict, child abuse

Individual Risk Factors

  • Difficult temperament/inflexibility, low positive mood, withdrawal 
  • Irritability 
  • Motor, language, and cognitive impairments 
  • Early aggressive behavior 
  • Poor social skills: impulsive, aggressive, passive, and withdrawn 
  • Poor social problem-solving skills 
  • Sensation-seeking 
  • Lack of behavioral self-control 
  • Early persistent behavior problems/antisocial behavior 
  • Attention deficit/hyperactivity disorder 
  • Poor impulse control/impulsivity, poor concentration 
  • Low self-esteem, perceived incompetence, negative explanatory and inferential style 
  • Poor grades/achievements/school failure, low commitment to school 

Peer Risk Factors

  • Substance-using peers
  • Attending college
  • Deviant peer group

Community Risk Factors

  • Law and norms about alcohol and drug use
  • Availability of the drug

Co-occurring DisordersThere is a high rate of co-occurring mental disorders among adolescent youth (12 to 18 years) who use substances or have a substance use disorder, including:

  • Conduct disorder
  • Attention deficit hyperactivity disorder
  • Major depressive disorder
  • Bipolar disorder
  • Anxiety disorder
  • Schizophrenia
  • Post-traumatic stress disorder (PTSD)

 In studies children 13 to 18 years of age with a mental disorder, rates of a co-occurring substance use disorder (SUD) have ranged from 61% to 88%.

Alcohol AbuseAlcoholism is etiologically complex, with a variety of other vulnerability factors

Environmental Factors

It has been estimated that there is a 7-fold risk of alcoholism in first-degree relatives of alcohol-dependent individuals, with male relatives of male alcohol-dependent individuals having the greatest risk for the disorder.

Genetic Factors

Among type 1 and type 2 alcoholics (typologies developed by Cloninger), type 1 alcoholics are characterized by the late onset of problem drinking, the rapid development of behavioral tolerance to alcohol, prominent guilt and anxiety related to drinking, and infrequent fighting and arrests when drinking. Cloninger also termed this subtype “milieu-limited,” which emphasizes the etiologic role of environmental factors. In contrast, type 2 alcoholics are characterized by early onset of an inability to abstain from alcohol, frequent fighting and arrests when drinking, and the absence of guilt and fear concerning drinking. Cloninger postulated that transmission of alcoholism in type 2 alcoholics was from fathers to sons, hence term the male-limited alcoholism.

Type 1 alcoholics are characterized by high-reward dependence, high-harm avoidance, and low-novelty seeking. In contrast, type 2 alcoholics are characterized by high-novelty seeking, low-harm avoidance, and low-reward dependence. Cloninger also hypothesized that specific neurotransmitter systems underlie personality structure. Specifically, dopamine is hypothesized to modulate novelty seeking, which is characterized by frequent exploratory behavior and intensely pleasurable responses to novel stimuli. Serotonin is hypothesized to modulate harm avoidance, which is a tendency to respond intensely to aversive stimuli and their conditioned signals. Finally, norepinephrine is hypothesized to modulate reward dependence or the resistance to extinction of previously rewarded behavior.

Pharmacological vulnerability

Some studies show a decreased sensitivity to the effects of alcohol in adult children of alcoholics. Other data indicate the effects of the alcohol metabolizing enzymes aldehyde dehydrogenase and alcohol dehydrogenase polymorphisms in individuals of Asian ancestry, in which aversive reactions to the effects of alcohol are associated with reduced risk of alcohol dependence. Flushing reaction happens to individuals homozygous for the gene that codes the enzyme, aldehyde dehydrogenase (ALDH2).This enzyme breaks down acetaldehyde, one of the byproducts of alcohol metabolism include the GABRG1 and GABRA2 genes that encode the gamma-1 and alpha-2 subunits of the GABA-A receptor, COMT Val158Met, and DRD2 Taq1A, which may affect dopamine receptor sensitivity, and KIAA0040. Genes may influence which individuals are more susceptible to alcohol-related comorbidities like alcoholic liver disease.

Affective Deregulation

It is proposed that alcoholism is caused by repeated use of alcohol to “self-medicate” negative affective states such as anxiety and depression.

Personality Disorders

These include hyperactivity, distractibility, sensation seeking, impulsivity, difficult temperament, and conduct disorder.[1][4][5]


Drug/Substance Abuse

Substantial proportions of youth surveyed had tried illicit drugs at least once in the countries that follow

  • Australia (greater than 40%),  
  • Canada (greater than35%),  
  • Europe (greater than 23% boys, 17% girls), 
  • United States (greater than 40%, more than 25% of 8th graders, 

Nearly half of 12th graders in the United States reported smoking marijuana daily, and 1 in 7 reported having been a daily marijuana smoker at some time for at least a month.

The rate of current illicit drug use among European youth ages 12 to 17 was 9.5% in 2012, with the percentage of users as follows:

  • 7.2% Marijuana
  • 2.8% Nonmedical use of the prescription drug (1.8 percent pain reliever)
  • 0.8% Inhalants
  • 0.6% Hallucinogens
  • 0.5% Heroin
  • 0.1% Cocaine

Alcohol Abuse

Alcohol use disorder is a common disorder in the United States. The 12-month prevalence of alcohol use disorder is estimated to be 4.6% among 12 to 17-year-olds and 8.5% among adults aged 18 years and older in the United States. Rates of the disorder are greater among adult men (12.4%) than among adult women (4.9%). Twelve-month prevalence of alcohol use disorder among adults decreases in middle age, being greatest among individuals 18 to 29-years-old (16.2%) and lowest among individuals age 65 years and older (1.5%). Twelve-month prevalence varies markedly across race/ethnic subgroups of the US population. For 12 to 17-year-olds, rates are greatest among Hispanics (6.0%) and Native Americans and Alaska Natives (5.7%) relative to whites (5.0%), African Americans (1.8%), and Asian Americans and Pacific Islanders (1.6%). In contrast, among adults, the 12-month prevalence of alcohol use disorder is clearly greater among Native Americans and Alaska Natives (12.1%) than among whites (8.9%), Hispanics (7.9%), African Americans (6.9%), and Asian Americans and Pacific Islanders (4.5%).

The 2011 US National Survey on Drug Use and Health estimated that of Americans over the age of 12 in the past 30 days:

  • 52.7% used alcohol at least once 
  • 23% reported binge drinking (defined by the survey as 5 or more drinks on one occasion
  • 6.2% reported heavy drinking (defined as 5 or more drinks on each of 5 or more days)


Drug/Substance Abuse

As with most behavioral and psychiatric disorders, the interplay between genetic risk, temperamental traits, and the environment may predispose to early use of substances of abuse. Once exposed to substances, brain reward systems reinforce substance use, resulting in repeated use and lower ability to control substance use.

Alcohol Abuse

The pathophysiology of alcohol use disorder is not known, but its development may be the result of a complex interplay of genetics, environmental factors, personality traits, and cognitive functioning.


Drug/Substance Abuse

Substance use and/or substance use disorders (SUDs) are associated with many negative consequences among youth, including accidents, death, health effects, crime, unplanned pregnancy, and lower achievement. Substance use contributes to accidents, death, and a variety of hazardous behaviors. Sexual behaviors are increased during adolescent substance use. Toxic effects of different drugs of abuse include following:

  • Opioids: Respiratory and central nervous system (CNS) depression, increased risk of aspiration due to diminished gag reflex, pupillary constriction, seizures, and euphoria
  • Barbiturates: Results in marked respiratory depression
  • Benzodiazepines: Results in minor respiratory depression
  • Amphetamine: Results in euphoria, grandiosity, pupillary dilation, prolonged wakefulness and attention, hypertension, tachycardia, anorexia, fever, and paranoia. Severe intoxication can cause cardiac arrest and seizures.
  • Cocaine: Impaired judgment, pupillary dilation, hallucinations, paranoid ideation, angina and sudden cardiac death
  • Caffeine: In restlessness and muscle twitching
  • Nicotine: restlessness
  • Phencyclidine: Violence, impulsivity, psychomotor agitation, nystagmus, tachycardia, hypertension, analgesia, psychosis, delirium, and seizures
  • LSD: Visual and auditory hallucinations, depersonalization, anxiety, paranoia, psychosis, and flashbacks
  • Marijuana: Euphoria, anxiety, paranoid delusions, the perception of slowed time, impaired judgment, amotivational syndrome, dry mouth, increased appetite, conjunctival injection, and hallucinations
  • MDMA: Euphoria, disinhibition, hyperactivity, life-threatening hypertension, tachycardia, hyperthermia, hypernatremia, and serotonin syndrome

Alcohol Abuse

Excessive alcohol consumption is the third leading preventable cause of death in the United States. More than 85,000 deaths a year in the United States are directly attributed to alcohol use.

  • Toxicity: Emotional lability, slurred speech, ataxia, blackouts[6][7]

History and Physical

Drug/Substance Abuse


A detailed history is necessary to establish the diagnosis of drug abuse. Patient’s social history can provide information about risk factors for unhealthy substance use and the impact of substance use on the patient’s role functioning. Look for Partner with a substance use disorder,  poor socio-economic society, violence, and high school alcohol and other drug availability. A family history of substance use disorder (SUD) has been shown to be a risk factor for the development of a Substance abuse disorder. Heritability estimates range from:

  • 50% to 70% for alcohol use disorder
  • From 34% to 78% for cannabis use disorder
  • 42% to 79% percent for cocaine use disorder
  • 23% to 54% for opioid use disorder

Dig deep into a history of Disrupted familial and social relationships, Failure to fulfill responsibilities at school or work (e.g., loss of job, poor grades in school. Ask questions about past history of violent behavior, child abuse, financial problems and sexual history (multiple partners, sex habits, etc.)

Physical Exam

During the physical examination, look for:

  • Poor personal hygiene
  • Significant weight loss or weight gain 
  • Signs of injection drug use including scars at injection sites (so-called “track marks”) on the skin
  • Signs of drug inhalation including atrophy of the nasal mucosa and perforation of the nasal septum
  • Evidence of acute intoxication or withdrawal, for example, slurred speech, unsteady gait, pinpoint pupils, bizarre or atypical behavior, changes in the level of arousal (agitation or sedation), tachycardia, euphoria, conjunctival injection, sweating, watery eyes, runny nose

Mental State Exam

This examination should be performed and look for following symptoms and signs:

  • Behavior: Aroused, agitated or sedated.
  • Appearance: Personal hygiene, clothes, 
  • Speech and Voice: Slurred or pressured
  • Mood: Euphoria, elated mood, depressed mood
  • Perception: Hallucination
  • Thoughts: Paranoia, delusions.
  • Insight: Poor insight
  • Cognition: Decreased concentration span, disorientation, amnesia
  • Judgment: Altered

Alcohol Abuse


Ask about current and past alcohol use and treatment, family history of alcohol problems and treatment, and a detailed history regarding the quantity and frequency of alcohol use.


Physical features accompanying alcohol abuse range from a normal physical exam to features of alcohol withdrawal (tachycardia, tremor, agitation, clouding of the sensorium) to features of the advanced liver disease in case of chronic alcoholism (spider angiomata, palmar erythema, gynecomastia, testicular atrophy, hepatic or splenic enlargement).[1]Go to:


DSM-5 Diagnostic Criteria for Substance Use Disorder

Two or more of the following in a 12-month period manifests a problematic pattern of use leading to clinically significant impairment or distress:

  1. Often taken in larger amounts or over a longer period than was intended
  2. A persistent desire or unsuccessful efforts to cut down or control use
  3. A great deal of time is spent in activities necessary to obtain, use, or recover from the substance’s effects
  4. Craving or a strong desire or urge to use the substance.
  5. Recurrent use resulting in a failure to fulfill major role obligations at work, school, or home
  6. Continued use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by its effects
  7. Important social, occupational, or recreational activities are given up or reduced because of use
  8. Recurrent use in situations in which it is physically hazardous.
  9. Continued use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance
  10. Tolerance
  11. Withdrawal

Disorder Severity: DSM-5 specifies mild, moderate, and severe based on the number of diagnostic criteria met by the patient at the time of diagnosis:

  • Mild: Two to 3 criteria 
  • Moderate: Four4 to 5 criteria       
  • Severe: Six or more criteria

DSM-5 Diagnostic Criteria for Alcohol Use Disorder

  1. Recurrent drinking resulting in failure to fulfill role obligations
  2. Recurrent drinking in hazardous situations 
  3. Continued drinking despite alcohol-related social or interpersonal problems
  4. Evidence of tolerance
  5. Evidence of alcohol withdrawal or use of alcohol for relief or avoidance of withdrawal
  6. Drinking in larger amounts or over longer periods than intended
  7. Persistent desire or unsuccessful attempts to stop or reduce drinking
  8. A great deal of time spent obtaining, using, or recovering from alcohol
  9. Important activities are given up or reduced because of drinking
  10. Continued drinking despite knowledge of physical or psychological problems caused by alcohol
  11. Alcohol Craving

Disorder Severity: The severity of alcohol use disorder at the time of diagnosis can be specified as a subtype based on the number of symptoms present: 

  • Mild: Two to 3 symptoms    
  • Moderate: Four to 5 symptoms
  • Severe: Six or more symptoms

Laboratory Tests

Substance Abuse

  • Drug of abuse screen
  • Urine drug levels
  • Blood drug levels
  • Hair drug levels
  • Saliva drug levels
  • Breath drug levels


Diagnosis of alcohol problem can be made in the outpatient department by using CAGE questionnaire which includes the questions: (need to) cut down, annoyance (on drinking), guilt (about drinking), an eye-opener

Screening tools like the 10 question Alcohol Use Disorder Identification Test (AUDIT) and the abbreviated 3-question audit-consumption (Audit-C) are recommended for screening.

Laboratory tests to confirm the diagnosis include:

  • Serum alcohol concentration
  • Direct alcohol biomarkers: Ethyl glucuronide.
  • Liver enzymes: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and albumin to test for liver damage. An AST: ALT ratio of 2:1 is indicative of alcohol-induced liver disease
  • Hemoglobin, complete blood count (CBC): To determine the presence and severity of anemia, pancytopenia, and macrocytosis. A mean corpuscular volume greater than 100 fL constitutes macrocytosis. Pancytopenia and macrocytosis usually require very heavy and prolonged use and often liver disease
  • Gamma-glutamyltransferase (GGT): Is an indicator of excessive alcohol use when elevated (normal reference ranges: 8 to 40 units/L for females and 9 to 50 units/L for males).
  • The patient’s social network, especially family, should be involved in treatment to the extent possible (and agreed to by the patient, if a legally competent adult), to provide additional history and therapeutic support and to help monitor the patient’s progress and adherence to treatment.[1][8]

Treatment / Management

Psychosocial Interventions   

  • Enhance motivation to reduce or end cannabis use  
  • Improve social skills  
  • Improve social support and interpersonal functioning
  • Manage painful feelings
  • Education about consequences of drug use

Cognitive-Behavioral Therapy

CBT is used to help patients learn how their thought processes play a role in developing their behavior. Cognitive awareness helps them to develop new ways of behaving, thus leading to change in thinking patterns and emotions.

Mutual Help Groups

Alcoholic Anonymous (AA), is a voluntary program for people with alcoholism/AUD, based on belief in a spiritual basis for recovery. Members attend meeting and experiences are shared and “Twelve steps towards Recovery” are discussed. Avoiding alcohol and benefits of avoiding alcohol are discussed. Abstinence is encouraged on a daily or weekly basis. Alcoholics Anonymous can be reached via their website

Motivational Interviewing/Motivational Enhancement

Drug or Addiction Counseling 


  • Alcohol: As many as 70% of individuals relapse after psychosocial treatment alone
  1. Naltrexone in toxicity and Supportive care.
  2. Naltrexone can be started while the patient is still drinking. Disulfiram should be used by abstinent patients to maintain abstinence, while acamprosate should be used once abstinence is achieved.
  3. Disulfiram should only be used in patients who are highly motivated to maintain abstinence.
  4. Treat Wernicke-Korsakoff with vitamin B-1 (thiamine) intravenously.
  • Opioids Intoxication: naloxone
  • Opioids Withdrawal: methadone
  • Barbiturate intoxication: Artificial ventilatory support.
  • Benzodiazepines intoxication: Flumazenil
  • Benzodiazepines withdrawal: Benzodiazepines having a long half-life. Gradually cutting dose down
  • Amphetamine intoxication: Benzodiazepines for agitation and seizures
  • Cocaine intoxication: Alpha-blockers and benzodiazepines
  • Caffeine intoxication: Symptomatic support
  • Nicotine intoxication: Symptomatic support
  • Nicotine withdrawal: Nicotine patch/gum, varenicline, bupropion
  • Phencyclidine intoxication: Benzodiazepines and rapid-acting antipsychotics
  • Marijuana: N-acetyl cysteine, gabapentin, and dronabinol[1][9][10]

Differential Diagnosis

  • Psychosis
  • Schizophrenia
  • Mania
  • Bipolar disorder
  • Organic brain disorder


Prognosis depends upon follow up and motivational and cognitive behavior therapy. Support like Alcoholics-Anonymous groups play an important role in prognosis.


Substance use leads to a number of problems among youth, including accidents, death, health effects, crime, unplanned pregnancy, and lower achievement.


Psychiatric consultation is necessary.

Deterrence and Patient Education

Cognitive behavioral therapy (CBT), motivational therapy, and psychotherapy are necessary to avoid remission.

Enhancing Healthcare Team Outcomes

The management of alcohol and drug abuse requires an interprofessional team that includes a mental health nurse, psychiastrist, emergency department physician, internist, addiction counselor and pain specialist. Clinicians need to be proactive and identify these patients; the earlier the treatment is undertaken, the better the outcomes. In addition, healthcare workers need to curtail the liberal prescription of analgesics, hypnotics, and sedatives and offer patients alternative means of managing their pain and insomnia.

Unfortunately, the outcomes for patients addicted to alcohol and drugs are poor. Short term recovery does occur, but relapses are common. Drug and alcohol addiction has repercussions beyond health; it can destroy the family, result in job loss and lead to financial loss.



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