In a new study published in the April 2010 issue of Elsevier’s Cortex researchers at the University of California San Francisco have shown that even prior knowledge of an impending distraction does not help to improve the working memory performance of older adults.

Drs. Theodore Zanto and Adam Gazzaley studied 21 adults aged between 60 and 80 years while they performed a working memory task in which they were shown random sequences of pictures containing faces and scenes. From a given sequence, participants were asked to remember either only the faces (ignoring scenes) or only the scenes (ignoring faces). In a second round of testing, the participants were given prior information about which specific pictures in the sequence would be relevant and which to ignore. The participants’ brain activity during the tasks was recorded using electroencephalograms (EEGs).

Previous research from this laboratory has indicated that the increase in brain activity in response to distractions occurs very soon (within 200 milliseconds) after the distraction appears. Since there is only a very short amount of time allotted for the brain to identify an item as irrelevant and suppress any further neural processing, it was suggested that older adults might benefit from prior knowledge of the impending distraction. However, results from the new study have proved that this is not the case.

Interestingly, the researchers found that later stages of neural processing (500-650 milliseconds after item presentation) do show signs of suppression, confirming that the “suppression deficit” is related to early stages of neural processing. The findings suggest that a working memory decline in older adults is indeed due to an inability to ignore distracting information, which furthermore cannot be improved with preparedness.

The researchers put rhesus monkey in a similar situation. The monkeys had to remember the number of dots in an image and reproduce the knowledge a moment later. While they were taking in the information, a distraction was introduced, showing a different number of dots. And even though the monkeys were mostly able to ignore the distraction, their concentration was disturbed and their memory performance suffered.

Measurements of the electrical activity of nerve cells in two key areas of the brain showed a surprising result: nerve cells in the prefrontal cortex signaled the distraction while it was being presented, but immediately restored the remembered information (the number of dots) once the distraction was switched off. In contrast, nerve cells in the parietal cortex were unimpressed by the distraction and reliably transmitted the information about the correct number of dots.

These findings provide important clues about the strategies and division of labor among different parts of the brain when it comes to using the working memory. “Different parts of the brain appear to use different strategies to filter out distractions,” says Dr. Simon Jacob, who carried out research in Tübingen before switching to the Psychiatric Clinic at the Charité hospitals in Berlin. “Nerve cells in the parietal cortex simply suppress the distraction, while nerve cells in the prefrontal cortex allow themselves to be momentarily distracted — only to return immediately to the truly important memory content.”

The researchers were surprised by the two brain areas’ difference in sensitivity to distraction. “We had assumed that the prefrontal cortex is able to filter out all kinds of distractions, while the parietal cortex was considered more vulnerable to disturbances,” says Professor Nieder. “We will have to rethink that. The memory-storage tasks and the strategies of each brain area are distributed differently from what we expected.”

Although the amygdala’s importance in face recognition and emotional assessment is well-known, little is understood about how these processes work, but research led by investigators at Cedars-Sinai and the California Institute of Technology has found that at least some of the brain cells that specialize in recognizing emotions may represent judgments based on the viewer’s preconceptions rather than the true emotion being expressed.

With colleagues from Huntington Memorial Hospital, using electrodes placed deep in the brain for unrelated diagnostic purposes, investigators recorded electrical activity of individual neurons and found a subset that were “emotion-selective” because their responses distinguished between happy and fearful faces.

Patients were shown pictures of faces whose emotion was difficult to recognize because only parts of the features were clearly visible. Some neurons were more active to faces showing fear, whereas others were more active to happy faces.

“In these instances, the patients correctly judged the expressed emotion,” said Ueli Rutishauser, PhD, assistant professor of neurosurgery and director of human neurophysiology research at Cedars-Sinai, senior author of an article published online the week of June 30 in the Early Edition of Proceedings of the National Academy of Sciences.

“But we found that these neurons also responded similarly during incorrect trials, when patients made errors about the actual emotion shown on the faces,” Rutishauser added. “When a fear face was incorrectly judged as happy, the neurons responded as if a happy face was correctly judged as happy — in a sense, “correctly” representing the patient’s incorrect judgment. When a happy face was incorrectly judged as a fear face, the neurons responded as if a fear face had been correctly judged as fear — again, reinforcing the ‘correctness’ of the incorrect decision. This tells us that the neurons’ responses were based on the subjective, perceived judgments that the patients made rather than on the ‘ground truth’ of the emotion shown in the stimulus.”

When the investigators recorded neurons in the hippocampus — a structure adjacent to the amygdala that also is involved in processing of thoughts, emotions and memories — they found that the cells responded to the visual stimuli, but those responses did not reflect the patients’ subjective judgment.

Abnormal functioning of the amygdala is implicated in several neurological diseases, such as autism, phobias, post-traumatic stress disorder and anxiety. According to the authors, this study provides an intriguing possibility for why amygdala dysfunction can lead to anxiety or unprovoked fear: Despite a normal sensory input — such as a happy-looking person — the internal representation of emotion in the amygdala is driven by the subjectively perceived emotion, which is fear in this case.

“To our knowledge, these findings are novel, in that they show that the response of emotion-sensitive neurons in the amygdala is biased toward the person’s subjective judgment of emotions instead of simply responding to the actual features of the stimulus,” said Shuo Wang, PhD, a postdoctoral scholar at Caltech and first author of the article. “We’ve known that the amygdala plays an important role in face and emotion recognition, but these results suggest that it integrates sensory information about faces. It may be that subjective perceptions of facial emotion are formed through repeated cycles of processing between the amygdala, the temporal cortex and other brain structures that shape a person’s values and social perspectives.”

The firing of a single neuron is believed to be the basic unit of brain computation, and these studies are accomplished through the collaboration of neuroscientists and neurosurgeons, with the consent and participation of patients who undergo deep brain electrode placement for diagnostic or treatment procedures.

“Single neuron studies have been performed in animals, but conducting them in human subjects gives us an opportunity to get direct feedback, without having to make assumptions when interpreting animal responses. The amygdala is a routine target for depth electrodes to localize epileptic seizures, and this provides the opportunity to explore this structure that is vitally important in the processing of emotions,” said Adam Mamelak, MD, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, one of the article’s authors.

According to Ralph Adolphs, PhD, Bren professor of psychology and neuroscience at Caltech, a contributing author, “Most data relevant to understanding psychiatric illness is derived from studies that use functional magnetic resonance imaging. What we desperately need is a more microscopic level as well, and these single-unit data we can record in neurosurgical patients offer a unique study opportunity.”

Rutishauser added, “Our group is focused on pursuing neurosurgical approaches that allow us to study individual neurons. We believe this research can provide valuable new knowledge on the function of the human nervous system that would otherwise be unobtainable.”

The DNA wraps around specialized proteins called histones in the cell’s nucleus. Normally, histones keep the DNA tightly packaged, preventing the expression of genes and the replication of DNA, which are required for cell growth and division. In order for these critical functions to take place, histones need to be modified with the attachment of an acetyl-group, donated by a critical molecule called acetyl-CoA. This attachment relaxes the DNA, allowing for DNA replication and gene expression. This mechanism is called “epigenetic regulation of DNA” and is important for normal functions (like the growth of an embryo or brain functions) or in common diseases like heart failure or cancer. Until now, how the nucleus generates acetyl-CoA for histone acetylation had remained elusive.

The research team, lead by postdoctoral fellow Gopinath Sutendra and professor Evangelos Michelakis in the Department of Medicine, discovered that an enzyme thought to reside only within mitochondria, called Pyruvate Dehydrogenase Complex (PDC), can actually find its way into the nucleus and do what it is designed to do in the mitochondria: generate acetyl-CoA. When in mitochondria, PDC uses the carbohydrates from our diet to generate acetyl-CoA for energy production. When in the nucleus, PDC can produce acetyl-CoA for histone acetylation.

“Although this jumping of an enzyme from one organelle into another in the cell is not unheard off, our results were quite surprising,” Sutendra says. “We wanted to measure acetyl-CoA levels and PDC in the mitochondria because that’s where we thought they were. But accidentally we had the nuclei isolated at the same time and we saw PDC in the nucleus. So we asked, ‘what is PDC doing there?’ And that started it all.”

“We were surprised that, despite the recognized importance of histone acetylation in cell biology and medicine, and despite the efforts by many to develop drugs that regulate histone acetylation, the source of acetyl-CoA in the nucleus had remained unknown,” Michelakis says. “Sometimes the answers to important biological questions are just next to you, waiting to be discovered,” he adds.

The team found that the translocation of PDC into the nucleus made cancer cells grow faster, an observation that may lead to additional strategies in the war against cancer. Yet, because the findings relate to how our DNA is regulated in general, this work may have far broader implications for many physiologic or pathologic conditions where epigenetic regulation is critical. “We are very excited about this new pathway linking energy production (the process known as metabolism) with gene regulation,” the researchers say.