Recommended Prostate-Specific Antigen Testing Intervals for the Detection of Curable Prostate Cancer H. Ballentine Carter, MD; Jonathan I. Epstein, MD; Daniel W. Chan, PhD; James L. Fozard, PhD; Jay D. Pearson, PhD Objective. p=m- Toevaluate prostate-specific antigen (PSA) testing intervals that curable cancer with less frequent test¬ maintain the detection of curable cancer and reduce unnecessary testing.
Hms.harvard.edua Different Voice Winter 2013
Vol. 19, No. 1
Joan of arc, the heroine who led the French measure the brain activity associated with the army to victory over the English at the battle of onset of hallucinations and compare it with neural Orléans in 1429, claimed that the voices of saints activity during hallucination-free periods. Many of compelled her to action. She was resolved to obey these studies, says Ann Shinn, an HMS instructor these messages, she said, because they were sent in psychiatry who studies auditory hallucinations directly from God. At the time, many believed the at McLean Hospital's Schizophrenia and Bipolar voices she heard were divinely inspired. Today, Disorders Program, show abnormal activity in the 1 A Different Voice many historians and psychiatric professionals superior temporal gyrus during auditory speculate that Joan of Arc experienced auditory 3 Neglect and the Brain hallucinations. This region of the brain is involved hallucinations symptomatic of schizophrenia.
in auditory processing, including language, and is 4 The David Mahoney Prize In scientiﬁc terms, a hallucination is the the location of the primary auditory cortex, a Symposium and Dinner perception of an object or event in the absence of region responsible for processing sounds.
5 Eric Kandel Receives 2012 an external stimulus. Auditory hallucinations, the "When you hear real sounds in the world— David Mahoney Prize most common form, are typically described as the sounds from the environment—the auditory cortex expression of one or more voices—a voice speaking is activated," says Shinn. "That same area of the 7 The Need to Eat one's own thoughts, one or more voices arguing, brain is stimulated during an auditory hallucination." or a voice narrating one's own actions.
Because hallucinations are spontaneous, Different causes, different content
transient, and unpredictable, the neural activity Auditory hallucinations are experienced by underlying them is difﬁcult to study. A number of approximately 70 percent of patients with what are referred to as symptom-capture studies, schizophrenia, a mental disorder characterized in however, offer a glimpse of what is happening part by an inability to differentiate between what in the brain during a hallucination. These studies is real and unreal. This type of hallucination also commonly manifests in people with bipolar disorder, certain major depressive illnesses, and post-traumatic stress disorder.
The voices that people with schizophrenia hear often articulate negative or derogatory content. Sometimes the voice is recognized as that of a family member or someone from the person's past; sometimes it is a voice that, although unfamiliar, has recognizable features (a deep, gruff tone, for instance). In extreme cases, the voice commands the person to commit destructive acts, which often causes considerable distress. Many who experience this type of hallucination feel they cannot escape it, a perception that can lead to depression, fear, anxiety, or anger. Some commit suicide to escape the voices.
continued on page 2 A Different Voicecontinued from page 1 Not all auditory hallucinations, however, stem the brain and speciﬁc mental functions. The team from mental illness, a fact that neurologist Oliver targeted an area deep within the auditory cortex Sacks addresses in his recent book, Hallucinations. called Heschl's gyrus, where the processing of Some studies, in fact, have found that 10 to 40 incoming auditory information begins.
percent of people without a diagnosable psychiatric In patients who experience auditory disorder experience auditory hallucinations. For hallucinations, Shinn found decreased functional these people, auditory hallucinations are caused connectivity between the left portion of Heschl's by such conditions as temporal lobe epilepsy, gyrus and the hippocampus, the brain region where delirium, dementia, focal brain lesions including coding and accessing memory occurs, as well as tumors, and infections such as viral encephalitis. decreased connectivity between the left portion of Withdrawal from alcohol, cocaine, and amphetamines Heschl's gyrus and the medial dorsal thalamus, which can also trigger such hallucinations. People without plays a role in abstract thinking and active memory. "This suggests there might be some abnormality involved in remembering stimuli," says Shinn, "some Currently, antipsychotic medications like Haldol (haloperidol), breakdown in the ability of those who hallucinate which are effective first-line therapies for schizophrenia, can act to remember where the sound originally came from." to calm hallucinations. These drugs block abnormal activity Shinn also found increased connectivity between Heschl's gyrus and two other brain regions, of dopamine, a neurotransmitter involved in regulating mood Broca's area and the cingulate gyrus. Broca's area and behavior. plays a signiﬁcant role in language comprehension, while the cingulate gyrus, an important part of the mental illness tend to report positive messages from limbic system, helps regulate emotions and initiates the voices they hear, and, as a result, are less likely the body's response to unpleasant experiences. to suffer distress or interference with their daily "We found evidence of abnormal connectivity activities than are people with psychiatric illnesses.
between the left Heschl's gyrus and the forebrain According to Shinn, however, hallucinations thalamocortical regions in patients prone to are not as well studied in nonpsychiatric patients auditory hallucinations," explains Shinn. "The data as they are in psychiatric patients. But she notes highlight the importance of interactions between that scientists are beginning to conduct research the left auditory cortex and brain circuitry involved on the latter population to determine whether the in speech and language, memory, and the monitoring neural substrate—the set of brain structures that of self-generated events." underlie speciﬁc behaviors and psychological Shinn's ﬁndings and those of others may help states—is similar to that found in mentally ill scientists develop new drugs to treat hallucinations. patients who experience hallucinations.
Currently, antipsychotic medications like Haldol (haloperidol), which are effective ﬁrst-line therapies A question of connectivity
for schizophrenia, can act to calm hallucinations. At McLean, Shinn and her colleagues recently These drugs block abnormal activity of dopamine, completed a study that compared three groups: a neurotransmitter involved in regulating mood schizophrenia patients who have had a lifetime of and behavior. "These medications aren't perfect," says auditory hallucinations, schizophrenia patients Shinn. "They don't quite get rid of the hallucinations, who have not experienced auditory hallucinations, but they do quiet them down." and healthy control subjects who have never Some consider hallucinations, especially those experienced a hallucination. The study design initiated by psychotropic drugs, to be expressions used fMRI to measure resting brain activity, an of a mind freed of ordinary patterns and structures; uncommon approach: Typically, study participants others who grapple with mental illness, may are asked to perform a discernible task while being consider them to be divine expressions or voices monitored by the scanner so that functional brain of personal doom; still others may ﬁnd them to be activity can be assessed. a non-threatening result of a medical condition. Instead of looking at brain structure, Shinn's Whatever the interpretation, the neural basis for team looked at functional connectivity; that is, the hallucination remains an area of intense study for relationship between activity in certain areas of Shinn and others.
neglect and the brain Should anyone need another reason for don't get that information, they're in a holding This article is part ensuring that children are nurtured and pattern in terms of brain development." of a series on the protected, a growing body of evidence suggests internal and external that neglect can harm brain development and Pruning the brain
forces that affect cause long-term detrimental effects to cognition Neurons are created during fetal development. the brain. and behavior.
These cells then migrate to various parts of the According to the National Children's Alliance, a brain and develop into specialized cells. Among nonproﬁt association dedicated to helping the ﬁrst to specialize are nerve cells in the communities ﬁght child abuse, there are more brainstem and midbrain, those regions that govern than 3.3 million reports of child abuse in the certain autonomic functions that allow a baby to United States each year, affecting nearly 6 million live. Other regions of the brain, ones that regulate children. More than 78 percent of these cases are emotion, thought, and language, develop after a considered neglect, deﬁned by the U.S. Department baby is born. During a child's early years, the of Health and Human Services as "a type of development of synapses, which are connections maltreatment that refers to the failure of caregivers between neurons, occurs at an astonishing rate. By to provide needed, age-appropriate care." age 3, a child's brain has trillions of synapses, some "In some ways," says Charles A. Nelson III, an of which are strengthened and remain intact, HMS professor of pediatrics and director of the others of which are discarded or pruned as part of Division of Developmental Medicine at Boston the normal development of the brain. While Children's Hospital, "neglect is worse than physical abuse. Kids are starved for information. If they continued on page 6 Other regions of the brain, ones that regulate emotion, thought, and language, develop after a baby is born. During a child's early years, the development of synapses, which are connections between neurons, occurs at an astonishing rate. By age 3, a child's brain has trillions of synapses, some of which are strengthened and remain intact, others of which are discarded or pruned as part of the normal development of the brain.
the David Mahoney Prize Symposium and Dinner —november 8, 2012 nobel laureate eric Kandel, MD, University Professor and Kavli Professor of brain Science, director, the Kavli institute Jeffrey Flier, MD, dean of the faculty of medicine for brain Science, and codirector, the Mind brain behavior at harvard University; Louise Mirrer, president initiative, Columbia University Medical Center, and Gerald of the new-York historical Society; and ambassador hildegarde Mahoney, chairman of Fishbach, MD, John e. borne Professor of Pharmacology the harvard Mahoney neuroscience and neuroscience at Columbia University Medical Center institute and ed rover, chairman and former director of the harvard Mahoney neuroscience and president of the Dana Foundation institute, take audience questions at hMni's 2012 symposium, and hMni council member "Progress in brain Science over the Past 50 Years." Guy McKhann, MD, professor of neurology and neuroscience at the Center for Mind–body research at Johns hopkins School of Public health; barbara de Portago; and Jerome LeWine ian robertson, PhD, professor of psychology, neuroscience institute, trinity College, Dublin; Suzanne McDonough; and James Watson nobel laureates James Watson and eric Kandel bob Merrill, h '81 (center), and his trio Liz Watson; William McDonough; and Fiona robertson, PhD table setting for the dinner honoring eric Kandel, recipient of the 10th Missie rennie taylor and Sharon King hoge David Mahoney Prize Photos on page 4 and 5 by Stephanie Badini. eric Kandel receives 2012 David Mahoney Prize the 10th biennial David Mahoney Prize was awarded to Eric R. Kandel, Nobel Laureate, author, university professor at Columbia University and Kavli Professor of Brain Science, director of The Kavli Institute for Brain Science, and codirector of The Mind Brain Behavior Initiative at Columbia University Medical Center, at a festive dinner in New York City on Thursday, November 8, 2012.
The dinner was preceded by a symposium— moderated by Edward Rover, Harvard Mahoney Neuroscience Institute council member and chairman of the Dana Foundation—at which Gerald Fishbach, John E. Borne Professor of Pharmacology and Neuroscience at Columbia University Medical Center and former director of HMNI, interviewed Kandel about the progress of neuroscience throughout the past 50 years. A lively question and answer period eric Kandel is presented with the 2012 David Mahoney Prize by hildegarde was followed by a pre-dinner reception with Mahoney, chairman of the harvard Mahoney neuroscience institute.
entertainment by Bob Merrill, H'81 and his jazz trio.
Hildegarde Mahoney, HMNI chairman, presented the David Mahoney Prize. Said Mahoney, "Eric, on behalf of everyone connected with the Harvard Mahoney Neuroscience Institute and myself, it is my pleasure to present you with the 2012 David Mahoney Prize, with which I know David would agree you so richly deserve. The plaque reads: Awarded to Eric Kandel for Building a Bridge Between the Public and Scientists Dedicated to Brain Research by HMNI." Among those attending the evening event were Jeffrey Flier, dean of the faculty of medicine at Harvard University; James Watson, Nobel laureate; Ian Robertson, founding director of the Neuroscience Institute at Trinity College, Dublin, and the College's dean of research and professor of psychology at the Institute; and Ambassador and Mrs. Alan Blinken. Jeffrey Flier, hildegarde Mahoney, eric Kandel, and Gerald Fishbach Melinda blinken and eric Kandel James Watson and Shirley rosenthal Neglect and the Braincontinued from page 3 synapses are forming, mature neurons become Nelson's studies with the Bucharest Early swathed in myelin, a fatty tissue that wraps Intervention Project, which examines the effects of neurons and helps ensure the clear, speedy institutionalization on the cognitive and behavioral transmission of signals along them. development of Romanian orphans, demonstrate the Also by age 3, the brain has almost reached its cascading negative effects that isolation and neglect ultimate physical size. The development of each can have on children. "Our studies show that these region of the brain, however, depends on kids don't know how to play with others, have no stimulation from the environment: face-to-face relationships with their caregivers, and have talk, repeated sounds, or responses to cries, for attachment problems that manifest in an inability example. Scientists think there are critical periods to form intimate relationships," he says. These during which the brain has a heightened sensitivity problems and others, including diminished cognitive to such stimuli but, compared with their function, low IQ, and executive function deﬁcits, understanding of these periods in non-human often continue into adolescence and adulthood.
A matter of gray and white
Two recent HMS studies shed some light on what According to a 2008 study by the American Professional happens to the brains of neglected children and Society on the Abuse of Children, babies who are ignored why the lack of a nurturing environment may when they begin to babble, often do not exhibit the rate of contribute to abnormal brain development. A language development that children should show between recent study by Nelson, published in July 2012 in the Proceedings of the National Academy of Sciences, the ages of 18 and 24 months. Other studies indicate that found that children raised in Romania's state-run children who suffer severe neglect have smaller brains and orphanages developed lower volumes of gray fewer neuronal pathways for learning. matter and white matter than children who grew up within families. White matter is responsible for the connectivity between different regions of the animals, are less certain when and for how long brain, while gray matter controls sensory perception these periods exist in human development. and other functions. Researchers do know, however, that without Nelson's team also found that children who experience-dependent learning, the brain is unable spent their infancy in orphanages but were later to strengthen synapses and neuronal pathways, transferred to high-quality foster care regained a potentially diminishing its functional capabilities. degree of white matter growth, showing that some of the damage from neglect and social isolation The price of neglect
can be reversed.
When environmental stimulation is lacking, the "What's missing in institutionalized children is brain's development can be altered, resulting in the nurturing and interaction required for normal, possible cognitive, social, and physical deﬁcits. healthy brain development," says Margaret Experience-dependent learning, for example, is Sheridan, an HMS instructor in pediatrics and lead critical for language development. According to a author on the PNAS paper. "Foster care addresses 2008 study by the American Professional Society that speciﬁc environment. The kids were still in on the Abuse of Children, a national organization Romania and their basic needs were still being of professionals who serve children and families met, but they had caregivers who were devoted to affected by child maltreatment and violence, babies one-on-one care and to tailoring solid interactions who are ignored when they begin to babble, often do not exhibit the rate of language development Nelson now plans to study institutionalized that children should show between the ages of 18 children as they enter adolescence to determine and 24 months. Other studies indicate that children how isolation and neglect affect executive function who suffer severe neglect have smaller brains and development and risk-taking behavior. "The fewer neuronal pathways for learning, and that transition to adolescence is hard anyway," he says. some children who do not have a nurturing "With a bad early beginning, these kids are at risk caregiver have difﬁculty forming meaningful for mental health problems as they get older. We relationships as they grow older.
need to see what fate awaits these kids." admit it. You ate too much over the holidays, animals led those animals to crave even more fat. indulging at parties and family gatherings and, In another study, a team at Scripps Research maybe, sneaking a hand—or two—into the cookie Institute found that animals that had access to tin. For a growing number of Americans, however, highly palatable foods for an hour a day binged on the need to eat, to launch that sneak attack on those foods despite being offered other food cookies or on food in general, is not a periodic options for longer periods of time. When another anomaly. It is an addiction, a potentially life- group of test animals in the Scripps study were threatening one, that is present year-round.
offered unlimited access to high-sugar, high-fat Although the American Psychiatric Association's foods, they became obese. In addition, when Diagnostic and Statistical Manual of Mental Disorders— threatened with electrical shocks, the animals the foremost reference for U.S. professionals who continued to prefer the high-sugar, high-fat choices. diagnose psychiatric conditions—does not include Brain scans of compulsive eaters as well as food addiction, there is mounting scientiﬁc evidence those of obese people reveal chemical surges in the that such a disorder exists. Through animal studies brain's reward circuit similar to those seen in the and imaging scans of the human brain, the idea brains of drug abusers. For example, cocaine ﬂoods that food can be addictive, like drugs or alcohol, this reward circuit with 2 to 10 times as much is gaining scientiﬁc muscle. In 2011 the National dopamine as is produced by other pleasurable Institute on Drug Abuse awarded grants totaling activities such as sex. The brain resets to adjust to nearly $6 million for investigations on the topic.
the dopamine overload, so, increasingly, more of The nonproﬁt organization Food Addiction the drug is needed to achieve a similar result. Institute says that people with this type of addiction In a key study in the early 2000s, a research lose control over their ability to stop eating certain team at Brookhaven National Laboratory found foods. Edward Khantzian, an HMS clinical professor that the brain scans of obese people show a lack of of psychiatry who studies addiction, sees parallels dopamine D2 receptors, a deﬁcit that mirrors one between addiction to food and dependence on drugs found in the brains of addicts. Dopamine D2 or alcohol. "People get hooked on food or drugs," he says, "because they ﬁnd it provides temporary comfort and relief, a lifting of some distressing Experiments in animals and humans show that, for some, psychological state." the same reward and pleasure centers in the brain that are The dopamine dance
activated by such addictive drugs as cocaine and heroin Experiments in animals and humans show that, for are also activated by certain foods, especially those high in some, the same reward and pleasure centers in the sugar, fat, and salt. brain that are activated by such addictive drugs as cocaine and heroin are also activated by certain foods, especially those high in sugar, fat, and salt. inhibits behavior, so an absence of receptors to These so-called highly palatable foods trigger the capture this form of dopamine means the urge to release of dopamine and similar neurotransmitters overeat—or to get high—cannot be curbed that, at certain levels, can induce euphoria. As a chemically in the brain. This deﬁcit also decreases person eating these foods experiences the pleasure a person's sensitivity to the rewards of either associated with increased dopamine concentrations eating or using drugs, requiring an ever-greater in the brain's reward centers, a craving to prolong use of food or drugs to generate the same level or intensify the pleasurable feelings takes hold, generating a cycle of overindulging that is hard to break. Packing on the pounds
In animal studies, researchers have discovered A hallmark of any addiction is the continued use that highly palatable foods cause biochemical of a substance regardless of the consequences. changes in the brain. In one experiment, Rockefeller "People continue the behavior," says Khantzian, University scientists found that, in response to "despite the costs, despite the harm to relationships, high-fat food consumption, animals produce employment, or personal health."certain substances in their brains. Reintroducing these substances by injecting them into test continued on page 8 on the brain correspondence/circulation nonproﬁt org.
US Postage Paid harvard Medical School 25 Shattuck Street, room 001 Future issues of On The Brain will be sent electronically. to continue receiving the newsletter, please send your email address to ann Marie Menting at The Need to Eat continued from page 7 neUroSCienCe inStitUte And the effects of food addiction, obesity, and Council Members: overeating, indeed, have consequences: They are hildegarde e. Mahoney, Chairman taking a toll on our nation's health. Obesity has Steven e. hyman, MD reached epidemic levels in the past 20 years. Today, Caroline Kennedy Schlossberg nearly two-thirds of U.S. adults are overweight, and ann McLaughlin Korologos 30 percent are obese. These people have a higher Joseph b. Martin, MD, PhD death rate than their ideal-weight counterparts and face a greater risk of diabetes, heart disease, and the diminished quality of life that poor health can bring. According to the American Heart On The Brain is published three times a year through the ofﬁce of Communications and external relations Association, a continuation of the current obesity at harvard Medical School, Gina Vild, associate trend could cause total health-care costs to top Dean and Chief Communications ofﬁcer.
Editor: ann Marie Menting Khantzian says there is hope, however. New Freelance Writer: Scott edwards drugs are being developed, including ezlopitant, a Design: Gilbert Design associates, inc. compound known to suppress cravings for alcohol In collaboration with: Michael e. Greenberg, that may also tamp down the neural pathways nathan Pusey Professor of neurobiology and Chair, Department of neurobiology involved in food addiction. And programs like Harvard Mahoney Neuroscience Institute Overeaters Anonymous, which models itself on the harvard Medical School 12-step programs for people with alcohol or drug 107 avenue Louis Pasteur addictions, offer hope for those who cannot otherwise stop eating.
Facts No One Can Ignore Any Longer Victory Over Cancer – Part One: Making the Unthinkable Possible Chapter I − Facts No One Can Ignore Any Longer The Sobering Cancer Death Statistics Cancer Is the Third Largest Cause of Death in of the World Health Organization (WHO) The Industrialised World • At the beginning of the 21st Century, the cancer epidemic