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  • 1. on the br ai n correspondence/circulation nonprofit org. Landmark Center US Postage Paid 401 Park Drive, Suite 22 West Boston, MA Boston, MA 02215 Permit No. 53825 For additional subscriptions or changes to the On the Brain mailing list, please contact Jennifer Montfort at 617-384-8483 or by e-mail at jennifer_montfort@hms.harvard.eduAnger and the Braincontinued from page 7 ON THE BRAIN harvard mahoney neuroscience institute Perlis cautions that the success of angermanagement and CBT depends on the quality of Council Members:the program­ who designed it, who runs it, how — Hildegarde E. Mahoney, Chairmanintensive it is, and the individual’s motivation. Steven E. Hyman, MD“You need to be motivated to change your Caroline Kennedy Schlossbergbehavior,” he says. “When you get to the point Ann McLaughlin Korologosthat you recognize what the anger is doing to Joseph B. Martin, MD, PhDyourself and others, that’s the time to get into ananger management program and when anger Edward F. Rovermanagement is most successful.” Daniel C. Tosteson, MD Other avenues for treating anger include Writers, Editorial Advisors:medications such as antidepressants and anti- Scott Edwards, Tamsen S. McMahon,convulsants, the latter of which help with Jennifer L. Montfortimpulsivity, and a class of drugs called serenics, Design:which Dougherty says work primarily through Gilbert Design Associates, Inc.dampening limbic system responses. Treating Harvard Mahoney Neuroscience Instituteunderlying mood disorders or depression can also Landmark Centerhelp alleviate angry outbursts. 401 Park Drive, Suite 22 Boston, MA 02215 Perlis says it is important to remember, however,that “everyone gets angry; not everyone needs Internet address: www.hms.harvard.edu/hmnitreatment.” Email address: hmni@hms.harvard.edu Views expressed by authors are their own and do not necessarily reflect views of HMNI.
  • 2. on the br ai nthe harvard mahoney neuroscience institute letterCognitive Neuroscience: Understanding Winter 2009 Vol. 15, No. 1Complex Human Behavior and the Brain contentsS ince the dawn of civilization, humankind friendship, self-defense and courage, vanity, has tried to answer vexing questions about the circumspection, sense of language, and kindness, 1   ognitive Neuroscience: C relationship between the body and the mind. among others. A person’s capacity for a given Understanding ComplexIn the last 20 years or so, the scientific and medical personality trait was determined by the size of that Human Behavior and  communities have made great strides in answering “brain organ,” and could be measured by the area the Brainthe question of how physical matter (the brain) of the skull that covered a given region of the brain 3   he Stress of Poverty   Trelates to mental (cognitive) phenomena such as in which the specific trait was thought to reside. Affects Childhood Brainperception, memory, learning and attention. In large While some of the assumptions of phrenology Developmentpart, the study of that relationship resides in the are still valid (such as certain mental processes 5   mall Amyloid Assemblies Srelatively new field of cognitive neuroscience. being localized in the brain), the shape of a person’s Provide New Target for “Cognitive neuroscience is a discipline that skull is not a reliable predictor of personality. Alzheimer’smerges psychology and basic neuroscience,” says “Gall and Spurzheim [Johann Gaspar SpurzheimDean F. Salisbury, PhD, an associate professor of was a German physician and chief proponent of 6   nger and the Brain Apsychiatry at Harvard Medical School and director phrenology] went overboard on localization,” saysof the Cognitive Neuroscience Laboratory at Salisbury. “They said that when you have more ofMcLean Hospital. “We’re trying to understand that personality trait, then that area of your braincomplex human behavior in the construct of is bigger. Looking at bumps on your head is a cuteplausible brain systems.” idea, but cognitive neuroscientists don’t have lot in Taking a multidisciplinary approach to the common with that extreme form of phrenology.”study of the brain and human behavior, cognitive While many cognitive neuroscientists stillneuroscience involves the study of internal mental follow the theory of localization, the more modernprocesses and the chemistry, physiology and continued on page 2anatomy of neurons and neural systems. It alsoexamines theories that explain the relationshipbetween the brain and behavior and comparesneural systems across species.A “cute idea”The roots of cognitive neuroscience lie in the samework as the now defunct field of phrenology inwhich personality traits were determined by“reading” bumps and fissures on an individual’sskull. Developed by German physician FranzJoseph Gall around 1800, phrenology was based onthe concept of localization; that is, that certainareas of the brain have specific, localized functions.Gall believed that the brain was made up of 27different “organs” that created an individual’spersonality. These organs included affection and
  • 3. Cognitive Neuroscience: Understanding Complex Human Behavior and the Braincontinued from page 1thinking is that behavior is governed by both psychiatrists are using the newer methods of MRI,local action and distributed networks throughout which provide better spatial resolution of activitythe brain. within the brain than earlier EEG-based tools.Imaging drives science Clarifying thought disorders through imagingAdvances in imaging technology have driven In the Cognitive Neuroscience Laboratory at McLeanmodern-day cognitive neuroscience. In the last 20 Hospital, Salisbury has spent the past 16 yearsyears, in fact, modern imaging techniques have studying brain structure and function, trying tosignificantly contributed to the emergence of determine what regions of the brain are abnormalcognitive neuroscience as a discipline. in mental illnesses such as schizophrenia and While a host of imaging methods are used, bipolar disorder and what the brain looks like inthree techniques—EEG, functional MRI, and the early courses of these diseases. Among otherstructural MRI—form the basis of much of the studies, he uses multimodal brain imaging towork done in cognitive neuroscience. The first, EEG examine cognitive-level thought disturbances.(electroencephalography), measures the electrical Thought disturbance is a cardinal symptom ofactivity produced by the brain. Abnormal EEG schizophrenia, a mental disorder characterized byresults can indicate irregular brain structures and abnormalities in the perception and expression ofcan be a sign of attention problems, seizure disorders, reality. The disease typically includes auditoryor confusion. Salisbury says EEG and extraction of hallucinations, paranoid or bizarre behavior, orspecific event-related brain activity from the EEG disorganized speech and thinking. Salisbury andlets scientists see electrical activity changes “at the his colleagues are combining behavioral measuresspeed of thought.” and brain activity measures to clarify the nature of Secondly, through advances in magnetic thought disorder and cognitive dysfunction inresonance imaging (MRI), researchers and clinicians schizophrenia with respect to actual brain structurecan see brain activity while a person is performing and function.certain functional tasks. Functional MRI (fMRI) is a Until recently, it was thought that schizophreniarelatively new procedure that uses MRI scans to was caused by poor interpersonal relationshipsmeasure metabolic changes that take place in an between the patients and their mothers. Betteractive part of the brain. This technology is used to imaging techniques, says Salisbury, allow researchersexamine the brain’s anatomy to determine which and clinicians to identify changes in the brains ofareas are handling critical functions such as thought, schizophrenics and develop interventions to haltspeech, movement and sensation. the process and possibly cure the disease. Thirdly, structural MRI maps the water volume If a specific brain function is localized to ainside the body. Because different tissues have certain area, MRI can measure that area to see ifdifferent amounts of water in them, structural MRI varying gray matter volumes lead to differentgives a very detailed image of these tissues. Unlike brainwave patterns. Bigger brain areas might notX-rays or CT scans, structural MRI is not affected mean better performance, Salisbury says, but evenby the skull bone and thus gives an extremely fine subtle pathology in the these areas generally leadspicture of brain structure, with the greatest contrast to functional consequences to which the brainbetween gray and white matter. Gray matter waves are sensitive.is akin to a computer, while white matter is like “If you believe the brain is important for humanthe cables connecting the different computer behavior,” he says, “then cognitive neuroscience iscomponents to one another. By providing the relevant. It’s important to think about humanhighest resolution of brain anatomy, Salisbury behavior and how it might be served by thesays, structural MRI is valuable for cognitive brain. Cognitive neuroscience gives us informationneuroscientists because is allows for very precise about the human condition based on plausiblemeasurement of brain volumes in specific areas. information about the brain. It helps us understand “EEG has been large in cognitive neuroscience how we work and helps us design interventionssince the late 1960s, early 1970s,” says Salisbury. based on the brain mechanisms involved.”“Other [technologies] that came along in the A long way, indeed, from feeling a bump on’90s have taken over.” He adds that increasing someone’s head. numbers of cognitive neuroscientists and research on the brain
  • 4. The Stress of Poverty Affects Childhood Brain DevelopmentT    of developmental diffi- culties among poor, disadvantaged childrenhas been chronicled for years. We don’t, says brain. In early childhood, the brain is genetically programmed to develop many more synapses than it will ever use, with different circuits being formedJack P. Shonkoff, MD, need another study simply in different areas of the brain at different times.documenting that association. This brain circuitry is influenced by a blend of “We’ve known for a very long time that there’s genetics and experience.a link between low income or low parent education “The brain expects the environment to influenceand poor school achievement as well as increased its evolving circuitry,” says Shonkoff. “These circuitsrisk for physical and mental health problems,” are literally shaped by personal experience.”says Shonkoff, the Julius B. Richmond FAMRI This process of circuit building results in whatProfessor of Child Health and Development and some scientists call biological embedding; that is,director of the Center on the Developing Child at experience gets built into our bodies and hasHarvard University. physiological effects on the brain as well as other The big question, he says, is why? What is it developing organ systems. Stable, predictable rela-about poverty and low parent education that leads tionships and a nurturing environment, he adds,to children having more problems in school and in may create stronger brain circuits. Likewise, soundlife? Shonkoff and his colleagues at the Center on circuits for learning may require an environmentthe Developing Child are among those who are with plentiful opportunities for interaction andtrying to understand the causal mechanisms that safe exploration.link highly stressful experiences with later problems Parents who are preoccupied with the dailyin learning, behavior and health. struggle of putting food on the table and shelter According to the National Poverty Center at over their family’s head often don’t have thethe University of Michigan, children represent a resources, education or time necessary to providedisproportionate percentage of the poor in the the kinds of experiences that could be required toUnited States. Children make up nearly one- facilitate healthy brain circuit development in theirquarter of the total U.S. population, but account children. Shonkoff says that in poor, less educatedfor 35 percent of the poor. In 2007, 13.3 million families there is reduced language interactionchildren, more than 17 percent of the children in between parents and children, and the stressesthe country, lived in poverty. associated with poverty can produce physiological responses that derail the healthy development ofThe developing brain brain circuitry.At the time of birth, the architecture of the human According to The Ounce of Prevention Fund,brain is underdeveloped. The brain, as it grows, is an organization dedicated to helping childrenconstantly wiring and refining the connections in low-income families overcome the challengesamong its trillions of nerve cells and the synapses continued on page 4through which messages are sent throughout the “The brain expects the environment to influence its evolving circuitry,” says Shonkoff. “These circuits are literally shaped by personal experience.” —Jack P Shonkoff, MD . ON THE BRAIN
  • 5. The Stress of Poverty Affects Childhood Brain Developmentcontinued from page 3of poverty and prepare for successful schooling, High quality programming to help“Infants and children who are rarely spoken to, the brain developwho are exposed to few toys, and who have little The principles of neuroscience inform “reasonablyopportunity to explore and experiment with their good” guidelines for clinicians and policymakersenvironment may fail to fully develop the neural who want to promote healthy brain developmentconnections and pathways that facilitate later in poor children, says Shonkoff. An environmentlearning. Despite their normal genetic endowment, of stable, nurturing relationships and variedthese children are at a significant intellectual opportunities for learning produce positive effects.disadvantage.” Healthy brain development can also be promoted by protecting children from chronic adversity. Exactly‘Toxic stress’ alters brain circuitry how to do this in the most effective way, however,Significant and continuing stress can have a has been a public policy challenge for decades.negative impact on early brain development. The The place to start is to think about howday-to-day adversity of severe poverty and communities support families with young children,parental mental health problems such as maternal says Shonkoff. Many times parents are not awaredepression, which has a higher prevalence among of how their interactions affect their children’spoor women, can compromise parent-child development. This includes talking and playinginteraction. The resulting lack of responsiveness— with them or reading to them at an early age. Inas well as violence, abuse, drugs and alcohol— situations where parents can’t provide what childrenis incredibly stressful for children, says Shonkoff. need, due to extreme poverty, substance abuse, Unrelenting stress in the absence of supportive mental illness, or violent relationships, interventionsrelationships with adults —referred to as “toxic targeting the source of the stress as well as thestress”—causes a prolonged activation of the needs of the family and children are essential.body’s stress response system, which includes the Universal access to prenatal and primaryrelease of stress hormones such as cortisol. Released health-care services is also essential, so all childrenby the adrenal gland, cortisol circulates in the can benefit from early diagnosis and preventivebrain during the body’s fight-or-flight response to measures, and affordable, accessible, high-qualitystress. Under normal circumstances, cortisol has childcare programs can provide nurturingshort-term benefits that help protect us from environments that promote learning. In a studydanger. When the cortisol system is repeatedly in the late 1990s, the National Center for Earlyactivated, however, levels of cortisol remain high Development and Early Learning found that,and can actually damage the brain. because childcare providers are often poorly “The area of the brain most sensitive to elevated trained, a majority of children in lower qualitycortisol is the hippocampus,” says Shonkoff, “the daycare programs “do not have the opportunity toregion of the brain where basic memory and early form the kind of comfortable, secure relationshipslearning circuits are developing. High levels of with a caregiver who will promote their healthycortisol can kill brain cells and disrupt circuit emotional development.”development in this region.” Shonkoff says that childcare and educational Constant adversity also produces what scientists programs for low-income children can be organizedcall allostatic load, or the physiological costs of “based on what the brain needs to develop in achronic stress, which include high blood pressure, healthy way.” The quality of these programs—inincreased heart rate, and elevated blood sugar and terms of staff training and stability, a language-richcortisol levels. Shonkoff says this may help explain environment, high ratio of adults to children, andwhy rates of hypertension, diabetes and heart disease safety, among other aspects—is essential.are higher in low-income populations. “Chronic “We know the characteristics of good qualityactivation of the stress response system precipitated programs,” he says, “and if a program has thoseby deep poverty,” he says, “causes phys­ological i features, we know it will be more successful inchanges that can affect the cardiovascular system, helping children develop.”brain circuits that influence learning and memory,and other metabolic systems.” on the brain
  • 6. Small Amyloid Assemblies Provide New Target for Alzheimer’sI n the early 1 990s, Dennis Selkoe, the Vincent and Stella Coates Professor of NeurologicalDiseases at Harvard Medical School and neurologist a key role in memory, attention, language and perceptual awareness. Two abnormal structures—plaques and tanglesat Brigham and Women’s Hospital, made a discovery —are the primary culprits that cause damage tothat provided an important clue to the development nerve cells in the brains of Alzheimer’s patients.of Alzheimer’s disease. He and a group of researchers Plaques, which build up between nerve cellsfound that even normal brain cells produce soluble (including outside the synapses), contain large,forms of amyloid beta-peptide (Abeta), the protein insoluble fibers of Abeta protein. Tangles are twistedfound in the plaques of patients with the disease, fibers of another protein, called tau, that form insideraising the possibility—since confirmed—that some nerve cells. Scientists have long debated whatAlzheimer’s might actually be a direct consequence roles plaques and tangles play in Alzheimer’s, butof Abeta over-production. Selkoe and his colleagues they now believe that plaques precede tangles andsoon showed that when mutant forms of certain that the two lesions act in concert to blockgenes are present in Alzheimer’s patients, the communication among nerve cells and disrupt thecellular production of Abeta is doubled, or more. activities required for neurons to survive. Now, Selkoe and his coworkers have taken that The early stages of Alzheimer’s occur whenknowledge a step further. Using extracts of human memory begins to diminish, although the patientbrain tissue obtained from patients who died of usually needs little or no assistance with dailyAlzheimer’s, Selkoe has found that dimers of Abeta, routines at that point. After diagnosis, patientsthe smallest possible assembly of the protein, can gradually progress beyond early-stage disease,lead to the dysfunction and loss of synapses that reaching a more advanced stage that is associatedare the hallmark of early Alzheimer’s disease. A with confusion, irritability, aggression, mood swings,synapse is the point of connection between two and long-term memory loss for which there isnerve cells through which chemical signals travel. currently no cure. Eventually, bodily functions are “Like most things with Alzheimer’s, these lost, ultimately leading to death.dimers [so-called because they consist of two smallmolecules that bond together] appear very early in Destructive dimersthe disease process, even many years before In their study, published in Nature Medicine in Juneclinical symptoms,” says Selkoe. “We don’t know 2008, Selkoe and his team, which included Ganeshprecisely how they induce synaptic dysfunction, Shankar, Shaomin Li and Bernardo Sabatini, all ofbut we speculate it is because they bind to Harvard Medical School, tested extracts of cerebralneuronal membranes and perturb important cortex taken from the brains of people who died ofproteins within them.” Alzheimer’s or other dementias, as well as those Selkoe says the findings are significant because without dementia. They found significant amountsthis is the first time Abeta assemblies have been of soluble Abeta in the brains of Alzheimer’sisolated from the brains of actual Alzheimer’s patients and little in any of the others.patients and their effects established. “Others have Previous postmortem brain studies showedstudied Abeta effects in genetically engineered that soluble forms of Abeta correlate most stronglymice or with synthetic Abeta in cell culture,” he with the cognitive symptoms of Alzheimer’s. Thesays, “but not from a human host. We feel this is researchers found that small soluble Abetathe real significance of the study.” assemblies taken from patients’ cortices inhibited long-term potentiation (LTP) and encouraged long-Plaques, tangles are culprits in Alzheimer’s term synaptic depression. LTP is an electrical correlateAlzheimer’s disease is a progressive, fatal disease of the strengthening of the connection betweenthat destroys brain cells, causing problems with two neurons and is commonly regarded as amemory, thinking, and behavior severe enough to surrogate for the cellular basis of memory. Long-interfere with daily life. According to the Alzheimer’s term synaptic depression is the selective weakeningAssociation, the disease affects nearly 5 million of neuronal synapses.Americans and begins its development in the “We’re not certain why these dimers are sohippocampus, the part of the brain responsible for destructive,” says Selkoe. “We think small is badmemory. From there, it appears to spread to the because the dimers are easily diffusible and can gocerebral cortex, the brain’s outer layer, which plays continued on page 7 on the brain
  • 7. Anger and the Brain This is the first in a series of articles on how T he physical sign s of anger are unmistak- able. Our heart rate increases, sometimes climbing from a normal 80 beats per minute to MD, a psychiatrist at Massachusetts General Hospital and associate professor at HMS. “Most people have intact, functional OFCs, so they are able to avoid internal and more than 180; our blood pressure elevates to frequent bouts of rage. Of course, our findings are external forces often dangerously high levels. Breathing becomes that patients who do have frequent bouts of rage,affect the brain. more rapid as we try to get additional oxygen into do not activate their OFCs to the degree that healthy our bodies, the muscles used for the fight-or-flight volunteers do.” reaction tighten, and the energy outburst can Perlis, whose work focuses on regions of the cause a deficiency in our blood sugar that makes brain influenced by genetics, says there is likely a us literally “shake” from anger. But, what is going genetic component that influences how we respond on in our brain when we get angry? to anger, either controlling our own or responding to others who are angry. Some studies suggest that twins are more likely to act similarly to hostility and anger than are unrelated people. “There is some inherited factor [that predisposes one to angry outbursts],” he says. “There’s some normal variation in the population, so we know it’s not pathological, just like we know there are some people who are 6 feet tall and others who are 5’9”.” Psychiatric disorders, including depression and bipolar disorder, influence how prone one is to anger. More than half of those with major depression report significant problems with irritability, says Perlis, so “as often as depression is about sadness, it can also be an angry state.” Bipolar disorder is also tied to anger, with irritability often being a primary “A lot goes into anger,” says Roy Perlis, MD, an feature of the illness. In addition, substance abuse assistant professor of psychiatry at Harvard Medical has a strong effect on anger and its consequences. School who studies anger and the brain. “There’s In general, Perlis adds, anger is a normal, the physical: the pounding heart, sweating, sometimes even healthy, emotion. “People shouldn’t gestures: and the mental: thinking about why be afraid to get angry,” he says. “We worry about you’re angry and what you’re going to do about it. it when it impacts the individual’s or others’ lives So, as far as the brain is concerned, anger is both or becomes pervasive.” cortical [higher cognitive aspects] and subcortical [physiological aspects].” Emotion and control Imaging studies have shown that in normal In 2004, Dougherty and his colleagues published individuals (those without underlying mental or findings in the Archives of General Psychiatry, showing physical illnesses), there is increased activity in the that people suffering from major depressive orbitofrontal cortex (OFC), the area of the brain disorder (MDD) and anger attacks have decreased behind the forehead that controls reasoning and blood flow to the OFC and amygdala, which other higher cognitive functions. At the same time, reduces their ability to control impulsive acts and blood flow to the amygdala, the almond-shaped the feelings about the consequences of their actions. region deep in the brain that controls emotions, Thus, they suffer both a lack of emotion and a lack also increases its activity. Angry emotions in the of control. Dougherty’s team found significantly less amgydala are thus cooled by activity in the OFC, activation of the OFC in patients with MDD with inhibiting our thoughts of rage. anger attacks when compared to a control group, But, why then, do we not fly into a fit of rage but did not find a difference in amygdala activation every time we become angry? between the groups. The amygdala came into play “Our, and others’, hypothesis is that the OFC when they looked at areas of the brain that plays a crucial role as a brake when our limbic correlated with OFC activation. In normal patients, system [which includes the amygdala] is active; that they found a healthy inverse reciprocal relationship is, when we are emotional,” says Darin Dougherty, in function between the two structures, whereas ON THE BRAIN
  • 8. this relationship was exactly the opposite in MDD Changing the way we think, feel, actpatients with anger attacks (with MDD patients While it is hard to change a habitual behavior suchwithout anger attacks falling in the middle). as anger, formal anger management programs that “We don’t know that the underlying neurobiology focus on reducing both emotional feelings and theof frequent rage attacks in patients with major physiological arousal that contributes to anger candepression with anger attacks is any different than help individuals control their reactions. Perlis saysthat in other populations who have frequent rage that anger management programs that are basedattacks,” says Dougherty. “In fact, studies of patients on cognitive behavioral therapy, or CBT, are oftenwith borderline personality disorder (BPD) or the most successful.intermittent explosive disorder (IED) exhibit results CBT is an umbrella term for several types ofvery similar to ours. We chose patients with major therapies. These are all based on the idea that ourdepression with anger attacks as a convenient thoughts, not external things like other people,vehicle for studying rage attacks, whereas others situations and events, cause our feelings andhave studied BPD and IED.” behaviors. The benefit of this is that we can change Harvard researchers, including Ronald Kessler, the way we think, feel and act even if the situationPhD, a professor of health-care policy at HMS, found doesn’t change.that IED, a disorder characterized by frequent bouts “The approach to anger would be to either lessenof angry and potentially violent outbursts, affects the limbic response, strengthen the brakes in thenearly 16 million adults and may predispose them OFC, or a combination of the two,” says Dougherty.to other mental illnesses and substance abuse. “CBT utilizes cortical regions, such as the OFC and other prefrontal areas, and strengthens them so they are better able to suppress limbic responses.” continued on page 8Small Amyloid Assemblies Provide New Target for Alzheimer’scontinued from page 5into the synaptic cleft, bind to membranes, and Four related clinical trials are currently beingcause local damage.” conducted in the United States and Europe to The HMS team also collaborated with scientists determine if an N-terminus antibody can neutralizeat University College Dublin to test human Abeta’s the adverse effects of Abeta dimers in Alzheimer’seffect on behavior. They injected soluble Abeta patients. Unpublished results of a Phase II study,dimers isolated from patients’ brains into the conducted by Elan Corporation and Wyethbrains of adult rats and found that the dimers Pharma­ euticals, showed some encouraging results cinduced certain characteristics of Alzheimer’s in in patients with mild to moderate stages ofthe rats, specifically disrupting the memories of Alzheimer’s.newly learned behaviors. The dimers, they further The HMS research has implications beyonddetermined, acted directly on synapses, damaging Alzheimer’s disease. The same Abeta process thatthe connections that are essential for neuron-to- causes Alzheimer’s, Selkoe says, can also contributeneuron communication. to age-related mild memory loss. “There are other reasons [for age-related memory loss] than Abeta,”Neutralizing Abeta he says, “but some percentage is represented byThe findings provide a potential new target for Abeta attacks on neuronal synapses.”anti-Alzheimer’s drugs, including antibodies that Selkoe says the next step in the research is toeffectively neutralize Abeta dimers, says Selkoe. fully purify Abeta dimers and trimers from patients’His team found that antibodies that target the first brains, label them with radioactive chemicals, andamino acid at the beginning of the Abeta protein bind them to slices of mouse brain to determineworked best at neutralizing the protein. which specific neuronal receptors are impaired by human Abeta. These receptors may provide additional targets to attack with drugs. on the brain