The amygdala, located deep below the brain surface in the temporal lobe, is classically associated with emotional and social behavior. In memory, its role was thought to be limited to learning and recalling experiences that invoked fear or other strong feelings. But the new study, published in the journal Nature Neuroscience, uncovered a much broader role for the amygdala in forming long-lasting memories in general.

In effect, the amygdala acts as a filter, tagging a small subset of ongoing experiences that end up being stored in long-term memory and thereby available for later retrieval.

“Our results demonstrate that the activity of specific kinds of neurons in the amygdala predicts, while the person sees an image for the first time, whether that image will later be remembered,” said Ueli Rutishauser, PhD, director of the Center for Neural Science and Medicine at Cedars-Sinai and the study’s corresponding author. “Such episodic autobiographical memories, such as where we parked our car or how we spent a recent family vacation, are critical to navigating everyday life and a sense of who we are.”

Investigators found that the brain’s ability to tag novel experiences for storage in long-term memory relies on specific types of neurons in the amygdala that respond selectively to specific categories of images, such as those showing faces, animals or landscapes. The stronger these category neurons reacted when a person viewed an image of the category to which the cell responded, the stronger that person's ability to later recall that image.

The study’s data comes from recordings of single-neuron activity in 112 surgical patients who had electrodes surgically implanted into their brains to monitor epileptic seizures. Participants were first presented with novel images they had never seen before and then asked to recall them later in the day.

This finding is an example of the power of collaboration between scientists and physicians: It was the data collected across over 100 patients that allowed this key new scientific discovery, which was replicated in two different datasets in the study.

Collecting this large amount of data was made possible by a multi-institutional consortium led by Cedars-Sinai and funded by the National Institutes of Health (NIH) Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) initiative.

“This is an impactful study that provides mechanistic insight into the role of the human amygdala—a region commonly associated with emotional responses—in determining which experiences and stimuli become lasting episodic memories. This rigorous human neuroscience study, which uses next-generation tools, has high potential to move discovery toward measurable health impacts,” said Mauricio Rangel-Gomez, PhD, program officer at NIH.

“Our findings have important clinical implications, as the memory impairments seen in disorders such as Alzheimer’s disease and temporal lobe epilepsy might be partly due to disrupted processes within the amygdala,” said Rutishauser, also a professor of Neurosurgery. “The amygdala might therefore be a suitable new target for treating these disorders using neuromodulation and/or cellular therapies.”

The research was led by Jiayang Xiao, PhD, who is the first author of the study.

Rutishauser added that future research could establish whether the amygdala plays a similar role in forming memories for other sensory modalities, such as sounds and smells.

“This study’s insights are the latest in a long line of research led by Cedars-Sinai and collaborators dedicated to revealing how human memory functions,” said Adam Mamelak, MD, director of the Epilepsy and Functional Neurosurgery Program and professor of Neurosurgery at Cedars-Sinai, and co-author of the study. “Beyond the pure scientific value of these breakthroughs, we are laser-focused on applying this new knowledge to improving the lives of patients.”

Additional Cedars-Sinai authors include Jonathan Daume, Natalia Kurilenko and Clayton Mosher.

Additional authors include Yousef Salimpour, William S. Anderson and Taufik A. Valiante.

Funding: This work was supported by the BRAIN Initiative through the National Institutes of Health (grant no. U01NS117839 to U.R.) and a Center for Neural Science and Medicine Postdoctoral Fellowship by Cedars-Sinai (to J.X.)

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“This is the best data to date on the question of surgery versus medical management in patients with this rare but serious condition,” said Adam Mamelak, MD, co-director of the Pituitary Center, director of the Functional Neurosurgery Program at Cedars-Sinai and lead author of the study. “It demonstrates in a prospective, controlled way what previous studies had begun to suggest, namely that pituitary apoplexy is very rarely a surgical emergency.”

The pituitary gland, located at the base of the brain, controls the function of several hormone-producing glands. Pituitary apoplexy occurs when a benign tumor in the pituitary gland area begins to bleed or dies, causing the tumor to grow and press on the surrounding brain tissues. This, in turn, causes symptoms such as severe headache, fatigue, confusion and vision problems that may include vision loss. Most commonly, these tumors are undetected prior to the apoplexy event.

To relieve the pressure on brain tissues and mitigate the symptoms of apoplexy, patients can either have the tumor surgically removed or be treated with medications to relieve pain and other symptoms while they wait for it to naturally shrink over time. In both cases, patients generally also need hormone-replacement therapy, Mamelak said.

Pituitary apoplexy has long been considered an emergency requiring rapid surgical treatment to achieve best results. Small retrospective studies, where investigators look back at previously collected data, have suggested that pituitary apoplexy patients have equally good outcomes with medical management, but these observations have failed to significantly change clinical practice.

“While we’ve seen a growing trend toward clinicians being a little more comfortable with medical management of pituitary apoplexy, in general, most patients still end up getting surgery,” Mamelak said. “Those small retrospective studies really didn’t move the needle that much.”

To provide a more solid basis for clinical decision-making, Mamelak and fellow investigators from the Department of Neurosurgery and the Pituitary Center at Cedars-Sinai—as well as colleagues from 11 other medical centers in North America, Japan, South Korea and Europe—developed the Pituitary Apoplexy Surgical Timing and Outcomes Registry (PASTOR).

The registry enrolled 97 patients with pituitary apoplexy at the time of diagnosis and compared outcomes for the 67 patients who had surgery with those for the 30 patients whose symptoms were medically managed. This type of prospective registry allows investigators to draw stronger conclusions because data collection is the same for all participants.

Investigators found that:

• Length of hospital stay was the same for patients who had surgery as for those who did not.
• Patients who had surgery experienced the same outcomes whether they had surgery right away or days after the onset of symptoms.
• There were no statistically significant differences in hormone function, vision or quality of life between the two groups of patients three and six months after treatment.

Mamelak noted that patients experiencing more severe vision symptoms were more likely to have surgery than those experiencing milder symptoms but that surgery didn’t necessarily lead to better outcomes.

“Cedars-Sinai and the other sites taking part in this study all have expert pituitary neurosurgery and endocrinology teams, which could help account for the positive outcomes experienced by surgical patients,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai. “A wealth of solid research tells us that outcomes from pituitary surgery are directly tied to surgical experience.”

Mamelak said that further research specifically looking at outcomes for people with visual field deficits would be needed to determine whether surgery is best in those cases. Meanwhile, the current findings could especially benefit medical centers that do not have the expertise to surgically treat pituitary tumors.

“These findings take some of the urgency out of managing these cases,” Mamelak said. “Clinicians at these centers now know that they can safely manage these patients medically and transfer them when it’s reasonable and available, or allow patients to forgo surgery entirely if they are comfortable with that.”

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