Inside the Minds of Murderers

Impulsive murderers much more mentally impaired than those who kill strategically

The minds of murderers who kill impulsively, often out of rage, and those who carefully carry out premeditated crimes differ markedly both psychologically and intellectually, according to a new study by Northwestern Medicine® researcher Robert Hanlon.

“Impulsive murderers were much more mentally impaired, particularly cognitively impaired, in terms of both their intelligence and other cognitive functions,” said Hanlon, senior author of the study and associate professor of clinical psychiatry and clinical neurology at Northwestern University Feinberg School of Medicine.

“The predatory and premeditated murderers did not typically show any major intellectual or cognitive impairments, but many more of them have psychiatric disorders,” he said.

Published online in the journal Criminal Justice and Behavior, the study is the first to examine the neuropsychological and intelligence differences of murderers who kill impulsively versus those who kill as the result of a premeditated strategic plan.

• Compared to impulsive murderers, premeditated murderers are almost twice as likely to have a history of mood disorders or psychotic disorders — 61 percent versus 34 percent.
• Compared to predatory murderers, impulsive murderers are more likely to be developmentally disabled and have cognitive and intellectual impairments — 59 percent versus 36 percent.
• Nearly all of the impulsive murderers have a history of alcohol or drug abuse and/or were intoxicated at the time of the crime — 93 percent versus 76 percent of those who strategized about their crimes.

Based on established criteria, 77 murderers from typical prison populations in Illinois and Missouri were classified into the two groups (affective/impulsive and premeditated/predatory murderers). Hanlon compared their performances on standardized measures of intelligence and neuropsychological tests of memory, attention and executive functions. He spent hours with each individual, administering series of tests to complete an evaluation. Hanlon has spent thousands of hours studying the minds of murderers through his research.

“It’s important to try to learn as much as we can about the thought patterns and the psychopathology, neuropathology and mental disorders that tend to characterize the types of people committing these crimes,” he said. “Ultimately, we may be able to increase our rates of prevention and also assist the courts, particularly helping judges and juries be more informed about the minds and the mental abnormalities of the people who commit these violent crimes.”

(Image: ALAMY)

A look inside children’s minds

University of Iowa study shows how 3- and 4-year-olds retain what they see around them

When young children gaze intently at something or furrow their brows in concentration, you know their minds are busily at work. But you’re never entirely sure what they’re thinking.

Now you can get an inside look. Psychologists led by the University of Iowa for the first time have peered inside the brain with optical neuroimaging to quantify how much 3- and 4-year-old children are grasping when they survey what’s around them and to learn what areas of the brain are in play. The study looks at “visual working memory,” a core cognitive function in which we stitch together what we see at any given point in time to help focus attention. In a series of object-matching tests, the researchers found that 3-year-olds can hold a maximum of 1.3 objects in visual working memory, while 4-year-olds reach capacity at 1.8 objects. By comparison, adults max out at 3 to 4 objects, according to prior studies.

“This is literally the first look into a 3 and 4-year-old’s brain in action in this particular working memory task,” says John Spencer, psychology professor at the UI and corresponding author of the paper, which appears in the journal NeuroImage.

The research is important, because visual working memory performance has been linked to a variety of childhood disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, developmental coordination disorder as well as affecting children born prematurely. The goal is to use the new brain imaging technique to detect these disorders before they manifest themselves in children’s behavior later on.

“At a young age, children may behave the same,” notes Spencer, who’s also affiliated with the Delta Center and whose department is part of the College of Liberal Arts and Sciences, “but if you can distinguish these problems in the brain, then it’s possible to intervene early and get children on a more standard trajectory.”

Plenty of research has gone into better understanding visual working memory in children and adults. Those prior studies divined neural networks in action using function magnetic resonance imaging (fMRI). That worked great for adults, but not so much with children,­ especially young ones, whose jerky movements threw the machine’s readings off kilter. So, Spencer and his team turned to functional near-infrared spectroscopy (fNIRS), which has been around since the 1960s but has never been used to look at working memory in children as young as three years of age.

“It’s not a scary environment,” says Spencer of the fNIRS. “No tube, no loud noises. You just have to wear a cap.”

Like fMRI, fNIRS records neural activity by measuring the difference in oxygenated blood concentrations anywhere in the brain. You’ve likely seen similar technology when a nurse puts your finger in a clip to check your circulation. In the brain, when a region is activated, neurons fire like mad, gobbling up oxygen provided in the blood. Those neurons need another shipment of oxygen-rich blood to arrive to keep going. The fNIRS measures the contrast between oxygen-rich and oxygen-deprived blood to gauge which area of the brain is going full tilt at a point in time.

The researchers outfitted the youngsters with colorful, comfortable ski hats in which fiber optic wires had been woven. The children played a computer game in which they were shown a card with one to three objects of different shapes for two seconds. After a pause of a second, the children were shown a card with either the same or different shapes. They responded whether they had seen a match.

The tests revealed novel insights. First, neural activity in the right frontal cortex was an important barometer of higher visual working memory capacity in both age groups. This could help clinicians evaluate children’s visual working memory at a younger age than before, and work with those whose capacity falls below the norm, the researchers say.

Secondly, 4-year olds showed a greater use than 3-year olds of the parietal cortex, located in both hemispheres below the crown of the head and which is believed to guide spatial attention.

"This suggests that improvements in performance are accompanied by increases in the neural response," adds Aaron Buss, a UI graduate student in psychology and the first author on the paper. "Further work will be needed to explain exactly how the neural response increases—either through changes in local tuning, or through changes in long range connectivity, or some combination."

Breaking habits before they start

Our daily routines can become so ingrained that we perform them automatically, such as taking the same route to work every day. Some behaviors, such as smoking or biting your fingernails, become so habitual that we can’t stop even if we want to.

Although breaking habits can be hard, MIT neuroscientists have now shown that they can prevent them from taking root in the first place, in rats learning to run a maze to earn a reward. The researchers first demonstrated that activity in two distinct brain regions is necessary in order for habits to crystallize. Then, they were able to block habits from forming by interfering with activity in one of the brain regions — the infralimbic (IL) cortex, which is located in the prefrontal cortex.

The MIT researchers, led by Institute Professor Ann Graybiel, used a technique called optogenetics to block activity in the IL cortex. This allowed them to control cells of the IL cortex using light. When the cells were turned off during every maze training run, the rats still learned to run the maze correctly, but when the reward was made to taste bad, they stopped, showing that a habit had not formed. If it had, they would keep going back by habit.

“It’s usually so difficult to break a habit,” Graybiel says. “It’s also difficult to have a habit not form when you get a reward for what you’re doing. But with this manipulation, it’s absolutely easy. You just turn the light on, and bingo.”

Graybiel, a member of MIT’s McGovern Institute for Brain Research, is the senior author of a paper describing the findings in the June 27 issue of the journal Neuron. Kyle Smith, a former MIT postdoc who is now an assistant professor at Dartmouth College, is the paper’s lead author.

Patterns of habitual behavior

Previous studies of how habits are formed and controlled have implicated the IL cortex as well as the striatum, a part of the brain related to addiction and repetitive behavioral problems, as well as normal functions such as decision-making, planning and response to reward. It is believed that the motor patterns needed to execute a habitual behavior are stored in the striatum and its circuits.

Recent studies from Graybiel’s lab have shown that disrupting activity in the IL cortex can block the expression of habits that have already been learned and stored in the striatum. Last year, Smith and Graybiel found that the IL cortex appears to decide which of two previously learned habits will be expressed.

“We have evidence that these two areas are important for habits, but they’re not connected at all, and no one has much of an idea of what the cells are doing as a habit is formed, as the habit is lost, and as a new habit takes over,” Smith says.

To investigate that, Smith recorded activity in cells of the IL cortex as rats learned to run a maze. He found activity patterns very similar to those that appear in the striatum during habit formation. Several years ago, Graybiel found that a distinctive “task-bracketing” pattern develops when habits are formed. This means that the cells are very active when the animal begins its run through the maze, are quiet during the run, and then fire up again when the task is finished.

This kind of pattern “chunks” habits into a large unit that the brain can simply turn on when the habitual behavior is triggered, without having to think about each individual action that goes into the habitual behavior.

The researchers found that this pattern took longer to appear in the IL cortex than in the striatum, and it was also less permanent. Unlike the pattern in the striatum, which remains stored even when a habit is broken, the IL cortex pattern appears and disappears as habits are formed and broken. This was the clue that the IL cortex, not the striatum, was tracking the development of the habit.

Multiple layers of control

The researchers’ ability to optogenetically block the formation of new habits suggests that the IL cortex not only exerts real-time control over habits and compulsions, but is also needed for habits to form in the first place.

“The previous idea was that the habits were stored in the sensorimotor system and this cortical area was just selecting the habit to be expressed. Now we think it’s a more fundamental contribution to habits, that the IL cortex is more actively making this happen,” Smith says.

This arrangement offers multiple layers of control over habitual behavior, which could be advantageous in reining in automatic behavior, Graybiel says. It is also possible that the IL cortex is contributing specific pieces of the habitual behavior, in addition to exerting control over whether it occurs, according to the researchers. They are now trying to determine whether the IL cortex and the striatum are communicating with and influencing each other, or simply acting in parallel.

“A role for the IL cortex in the regulation of habit is not a new idea, but the details of the interaction between it and the striatum that emerge from this analysis are novel and interesting,” says Christopher Pittenger, an assistant professor of psychiatry and psychology at Yale University School of Medicine, who was not part of the research team. “Thinking in the long term, it raises the question of whether targeted manipulations of the IL cortex might be useful for the breaking habits — and exciting possibility with potential clinical ramifications.”

The study suggests a new way to look for abnormal activity that might cause disorders of repetitive behavior, Smith says. Now that the researchers have identified the neural signature of a normal habit, they can look for signs of habitual behavior that is learned too quickly or becomes too rigid. Finding such a signature could allow scientists to develop new ways to treat disorders of repetitive behavior by using deep brain stimulation, which uses electronic impulses delivered by a pacemaker to suppress abnormal brain activity.

Researchers Find Zinc’s Crucial Pathway to the Brain

A new study helps explain how parts of the brain maintain their delicate balance of zinc, an element required in minute but crucial doses, particularly during embryonic development.

The study, led at the Marine Biological Laboratory (MBL) by Mark Messerli in collaboration with scientists from the University of California, Davis, shows that neural cells require zinc uptake through a membrane transporter referred to as ZIP12. If that route is closed, neuronal sprouting and growth are significantly impaired and is fatal for a developing embryo. Their discovery was published in the Proceedings of the National Academy of Sciences.

“This particular transporter is an essential doorway for many neurons in the central nervous system,” explains Messerli. “You knock out this one gene, this one particular pathway for the uptake of zinc into these cells, and you essentially prevent neuronal outgrowth. That’s lethal to the embryo.”

Previously, scientists thought that zinc could use more than one pathway to enter the cell during early brain development. Some other elements, like calcium, enjoy such luxury of multiple options.

Knocking out ZIP12, affected several critical processes in the brain, the scientists found. For example, frog embryos were unable to develop their neural systems properly. Additionally, neurons had trouble reaching out to connect to other neurons; their extensions were both shorter and fewer in number than normal.

“We were surprised that ZIP12 was required at such an early and critical stage of development,” said Winyoo Chowanadisai, a researcher in nutrition at the University of California at Davis and visiting scientist in the Cellular Dynamics Program at the MBL. Dr. Chowanadisai was the first on the team to realize that ZIP12 is expressed in such abundance in the brain.“This study also reinforces the importance of periconceptional and prenatal nutrition and counseling to promote health during the earliest stages of life.”

ZIP12 is part of a larger family of transporters involved in the movement of metal ions from outside the cell. Other reports showed that simultaneously blocking 3 other transporters in the family – including  ZIP1, 2, and 3 – had no major effects on embryonic development.

Zinc is needed for healthy neural development, helping the brain to learn and remember new information. However, too much zinc can also be problematic.

The research team is investigating the implications of their results on processes like embryonic brain development and wound healing.

“[The result] was not expected,” said Messerli, a physiologist in the MBL’s Bell Center for Regenerative Biology and Tissue Enginering and Cellular Dynamics Program. ““We found that zinc uptake through ZIP12 is a regulatory point for neuronal growth, required for development and possibly required for learning and memory throughout life. We want to elucidate the downstream targets that zinc is affecting. That’s the next exploration.”

Alzheimer’s Disease Mouse Models Point To A Potential Therapeutic Approach

Building on research published eight years ago in the journal Chemistry and Biology, Kenneth S. Kosik, Harriman Professor in Neuroscience and co-director of the Neuroscience Research Institute (NRI) at UC Santa Barbara, and his team have now applied their findings to two distinct, well-known mouse models, demonstrating a new potential target in the fight against Alzheimer’s and other neurodegenerative diseases.

The results were published online June 4 as the Paper of the Week in the Journal of Biological Chemistry. As a Paper of the Week, Kosik’s work is among the top 2 percent of manuscripts the journal reviews in a year. Based on significance and overall importance, between 50 and 100 papers are selected for this honor from the more than 6,600 published each year.

Kosik and his research team focused on tau, a protein normally present in the brain, which can develop into neurofibrillary tangles (NFTs) that, along with plaques containing amyloid-ß protein, characterize Alzheimer’s disease. When tau becomes pathological, many phosphate groups attach to it, causing it to become dysfunctional and intensely phosphorylated, or hyperphosphorylated. Aggregations of hyperphosphorylated tau are also referred to as paired helical filaments.

"What struck me most while working on this project was how so many people I’d never met came to me to share their stories and personal anxieties about Alzheimer’s disease," said Xuemei Zhang, lead co-author and an assistant specialist in the Kosik Lab. "There is no doubt that finding therapeutic treatment is the only way to help this fast-growing population." Israel Hernandez, a postdoctoral scholar of the NRI and UCSB’s Department of Molecular, Cellular and Developmental Biology, is the paper’s other lead co-author.

Treatments for hyperphosphorylated tau, one of the main causes of Alzheimer’s disease, do not exist. Current treatment is restricted to drugs that increase the concentration of neurotransmitters to promote signaling between neurons.

However, this latest research explores the possibility that a small class of molecules called diaminothiazoles can act as inhibitors of kinase enzymes that phosphorylate tau. Kosik’s team studied the toxicity and immunoreactivity of several diaminothiazoles that targeted two key kinases, CDK5/p25 and GSK3ß, in two Alzheimer’s disease mouse models. The investigators found that the compounds can efficiently inhibit the enzymes with hardly any toxic effects in the therapeutic dose range.

Treatment with the lead compound in this study, LDN-193594, dramatically affected the prominent neuronal cell loss that accompanies increased CDK5 activity. Diaminothiazole kinase inhibitors not only reduced tau phosphorylation but also exerted a neuroprotective effect in vivo. In addition to reducing the amount of the paired helical filaments in the mice’s brains, they also restored their learning and memory abilities during a fear-conditioning assay.

According to the authors, the fact that treatment with diaminothiazole kinase inhibitors reduced the phosphorylation of tau provides strong evidence that small molecular kinase inhibitor treatment could slow the progression of tau pathology. “Given the contribution of both CDK5 and GSK3ß to tau phosphorylation,” said Kosik, “effective treatment of tauopathies may require dual kinase targeting.”

Madison Cornwell, a Beckman Scholar with UCSB’s Center for Science and Engineering Partnerships who worked in Kosik’s lab, added: “As a beginning step, we demonstrated that two of these compounds were successful in clearing the brain of tau tangles in a mouse model, but someday inhibitors of these kinases may serve to ameliorate the symptoms of Alzheimer’s disease in patients.”

Promising Alzheimer’s ‘drug’ halts memory loss

A new class of experimental drug-like small molecules is showing great promise in targeting a brain enzyme to prevent early memory loss in Alzheimer’s disease, according to Northwestern Medicine® research.

Developed in the laboratory of D. Martin Watterson, the molecules halted memory loss and fixed damaged communication among brain cells in a mouse model of Alzheimer’s.

"This is the starting point for the development of a new class of drugs," said Watterson, lead author of a paper on the study and the John G. Searle Professor of Molecular Biology and Biochemistry at Northwestern University Feinberg School of Medicine. "It’s possible someday this class of drugs could be given early on to people to arrest certain aspects of Alzheimer’s."

Changes in the brain start to occur ten to 15 years before serious memory problems become apparent in Alzheimer’s.

"This class of drugs could be beneficial when the nerve cells are just beginning to become impaired," said Linda Van Eldik, a senior author of the paper and director of the University of Kentucky Sanders-Brown Center on Aging.

The study is a collaboration between Northwestern’s Feinberg School, Columbia University Medical Center and the University of Kentucky. It will be published June 26 in the journal PLOS ONE.

The novel drug-like molecule, called MW108, reduces the activity of an enzyme that is over-activated during Alzheimer’s and is considered a contributor to brain inflammation and impaired neuron function. Strong communication between neurons in the brain is an essential process for memory formation.

"I’m not aware of any other drug that has this effect on the central nervous system," Watterson said.

"These exciting results provide new hope for developing drugs against an important molecular target in the brain," said Roderick Corriveau, program director at the National Institute of Neurological Disorders and Stroke, which helped support the research. "They also provide a promising strategy for identifying small molecule drugs designed to treat Alzheimer’s disease and other neurological disorders."

Watterson and his collaborators have a new National Institutes of Health (NIH) award to further refine the compound so it is metabolically stable and safe for use in humans and develop it to the point of starting a phase 1 clinical trial.

(Image: Jay Vollmar)