H.M.’s Brain Yields New Evidence
3D model of famous amnesiac’s brain helps illuminate human memory
During his lifetime, Henry G. Molaison (H.M.) was the best-known and possibly the most-studied patient of modern neuroscience. Now, thanks to the postmortem study of his brain, based on histological sectioning and digital three-dimensional construction led by Jacopo Annese, PhD, at the University of California, San Diego, scientists around the globe will finally have insight into the neurological basis of the case that defined modern studies of human memory.
The microscopic anatomical model of the whole brain and detailed 3D measurements of the medial temporal lobe (MTL) region are described in a paper to be published online in Nature Communications on January 28.
H.M. was an epileptic patient whose severe and almost total amnesia was the unexpected result of a bilateral surgical ablation of the MTL, including the hippocampus, in 1953. Until his death in 2008, the purity and severity of H.M.’s memory impairment, along with his willingness to participate in continual testing, made his case uniquely influential.
While his intellectual abilities, personality, language and perceptual skills remained intact, he was unable to store information in long-term memory. After his brain operation, H.M. was profoundly impaired in forming new declarative memories. This unfortunate outcome became the catalyst for over 50 years of scientific discoveries (and thousands of publications) that have radically changed scientists’ basic understanding of memory function. His case was significant because it provided the first conclusive evidence for the involvement of the hippocampus in forming new memories.
In December 2009, Annese and his team dissected H.M.’s brain into 2,401 thin tissue slices that were then preserved cryogenically in serial order. While the brain was being sliced, the researchers collected an unabridged series of digital images of the surface of the block, corresponding to each tissue section. These images were archived and used to create a three-dimensional microscopic model of the whole brain. The model of H.M.’s brain contains clues to help understand the surgery performed in 1953, and the level of sampling and image quality afforded by this study represents a significant advance over the MRI scans performed with H.M. when he was alive.
Anthony Chetti is one of the beneficiaries of tractography-guided brain surgery. Chetti developed a tumor in the region of the brain called the occipital lobe, the portion of the brain responsible for processing visual information.
“Anytime that you are told that you can potentially lose your vision, you are scared,” said Chetti, a San Diego school teacher. “But when Dr. Chen shared the tractography images with me and showed me how he was going to avoid injury to the connection between my eye and the occipital lobe, I was reassured.”
Chetti underwent a complete excision of the brain tumor without any damage to his vision.
“When I woke up from surgery, I asked for my glasses immediately and began running systems checks. I could see the clock. I could read the words on a sign. It was immediately evident that there were no problems,” said Chetti.
Tractography scans can reveal tiny open paths between nerve fibers to reach brain tumors. The scans are color coded and display tiny neural connections. Other current imaging techniques such as computed tomography (CT) and conventional magnetic resonance imaging (MRI) cannot achieve this type of visual display.
Brain cells of a laboratory mouse glowing with multicolor fluorescent proteins. Image courtesy of Harvard University, Livett-Weissman-Sanes-Lichtman
Early growth factor treatment may help prevent cell loss in Alzheimer’s disease
Four years ago, Mark Tuszynski, MD, PhD, professor of neurosciences at UC San Diego School of Medicine and director of the Center for Neural Repair and colleagues showed that a BDNF-based treatment measurably improved neural dysfunction in animal models of Alzheimer’s disease. The findings garnered international headlines.
Now there is new evidence that BDNF may be effective as a preventive measure for AD.
In a paper, published yesterday in The Journal of Neuroscience, Tuszynski and colleagues follow up with evidence that early life BDNF treatment prevents neuronal loss in mutant mice genetically predisposed to early-onset familial Alzheimer’s disease.
Specifically, mice engineered to express APP, a protein strongly linked to AD development, received injections of the BDNF gene at two months of age and were examined five months later. The researchers found that BDNF-treated mice exhibited better behavior and brain function than untreated APP mutant mice and suffered significantly less neuron loss in the entorhinal cortex, a region of the brain that helps mediate learning and memory.
In addition, they noted that BDNF did not affect amyloid plaque accumulation, another major indicator of AD, suggesting that direct amyloid reduction is not necessary to achieving significant neuroprotective benefits in mutant amyloid models of AD.
“These findings strengthen the rationale for planning human clinical trials of BDNF therapy in AD,” said Tuszynski. “This is an effort that we are actively engaged in.”
Tuszynski also noted that there is a possibility that BDNF therapy and anti-amyloid therapies for AD could be combined to yield better treatments than either treatment alone.
Human astrocyte progenitors and immature astrocytes, created from induced pluripotent stem cells, form an “astrosphere” inside a Petri dish. Image courtesy of the University of Wisconsin-Madison.
A star (cell) is born
Astrocytes are star-shaped (the name derives from the Greek words for star and cell) glial cells. They are the most abundant cell type in the human brain, and for good reason: They have a lot of jobs, from providing biochemical support of the endothelial cells that form the blood-brain barrier to delivering nutrients to nervous system tissue to helping repair the spinal cord after traumatic injury.
Neurons attract most of the attention, but researchers are increasingly investigating the roles and potential of astrocytes in treating a host of neurological harms and diseases.
For example, a CIRM-supported “disease team” of scientists at UC San Diego School of Medicine and the Salk Institute for Biological Studies is investigating the possibility of transplanting healthy astrocytes derived from stem cells into patients suffering from amytrophic lateral sclerosis or Lou Gehrig’s disease. The work is based, in part, upon encouraging findings in an ALS mouse model, conducted by Don Cleveland, PhD, and colleagues.
More recently, UC Davis scientists underscored the potential therapeutic value of astrocytes, reporting in the journal Nature Communications that the cells’ “calm” nature may make them best suited for some future stem cell-based neurological therapies.
“Astrocytes are often considered just ‘housekeeping’ cells because of their supportive roles to neurons, but they’re actually much more sophisticated,” said study co-author Wenbin Deng in a news release.
“They are critical to several brain functions and are believed to protect neurons from injury and death. They are not excitable cells like neurons and are easier to harness. We wanted to explore their potential in treating neurological disorders, beginning with stroke.”
Of course, success is neither guaranteed nor looming, but if it happens, astrocytes will have a starring role.
These photomicrographs depict comparative stained sections of a healthy brain (top) and of patient EP, in which significant structures in the medial temporal lobe are heavily damaged or missing. The letters identify specific brain structures, such as EC and PRC for entorhinal cortex and perirhinal cortex, respectively, both important to memory formation and function.
Gone, But Not Forgotten
UC San Diego scientists recall EP, perhaps the world’s second-most famous amnesiac
An international team of neuroscientists has described for the first time in exhaustive detail the underlying neurobiology of an amnesiac who suffered from profound memory loss after damage to key portions of his brain.
Writing in this week’s Online Early Edition of PNAS, principal investigator Larry R. Squire, PhD, professor in the departments of Neurosciences, Psychiatry and Psychology at the University of California, San Diego School of Medicine and Veteran Affairs San Diego Healthcare System (VASDHS) – with colleagues at UC Davis and the University of Castilla-La Mancha in Spain – recount the case of EP, a man who suffered radical memory loss and dysfunction following a bout of viral encephalitis.
EP’s story is strikingly similar to the more famous case of HM, who also suffered permanent, dramatic memory loss after small portions of his medial temporal lobes were removed by doctors in 1953 to relieve severe epileptic seizures. The surgery was successful, but left HM unable to form new memories or recall people, places or events post-operation.
HM (later identified as Henry Gustav Molaison) was the subject of intense scientific scrutiny and study for the remainder of his life. When he died in 2008 at the age of 82, he was popularized as “the world’s most famous amnesiac.” His brain was removed and digitally preserved at The Brain Observatory, a UC San Diego-based lab headed by Jacopo Annese, PhD, an assistant adjunct professor in the Department of Radiology and a co-author of the PNAS paper.
Like Molaison, EP was also something of a scientific celebrity, albeit purposefully anonymous. In 1992, at the age of 70, he was diagnosed with viral encephalitis. He recovered, but the illness resulted in devastating neurological loss, both physiologically and psychologically.
Not only did he also lose the ability to form new memories, EP suffered a modest impairment in his semantic knowledge – the knowledge of things like words and the names of objects. Between 1994, when he moved to San Diego County, and his death 14 years later, EP was a subject of continued study, which included hundreds of different assessments of cognitive function.
“The work was long-term,” said Squire, a Career Research Scientist at the VASDHS. “We probably visited his house 200 times. We knew his family.” In a 2000 paper, Squire and colleagues described EP as a 6-foot-2, 192-pound affable fellow with a fascination for the computers used in his testing. He was always agreeable and pleasant. “He had a sense of humor,” said Squire.
How cancer hijacks healthy cell circuits to stay alive
Fundamentally, cancer is a disease of cell growth and function run amok. Frequently, the culprit is mutations in the proteins that regulate growth, such as epidermal growth factor receptor or EGFR, which has been implicated in a variety of cancers.
Among these is glioblastoma multiforme (GBM), a highly malignant brain cancer that has thus far defied satisfactory remedy. More than 9,000 new cases of GBM are diagnosed each year in the United States and effective treatments are limited. GBM tumors are aggressive and resistant to current therapies, such as surgery, radiation and chemotherapy. The median survival rate for newly diagnosed GBM patients is just 14 months.
Drugs devised to block mutant growth signals in GBM have so far proven only temporarily effective. Eventually, cancer cells adapt and overcome. Most current research has focused on how mutations in other proteins in cancer cells allow them to become drug resistant.
In a new paper, published in Cancer Discovery, a team of scientists co-led by Paul Mischel, MD, a principal investigator at the Ludwig Institute for Cancer at the University of California, San Diego and a professor of pathology in the UC San Diego School of Medicine, identify a unique mechanism that allows GBM cells to develop resistance to drugs targeting EGFR signaling.
The feat, according to Mischel and co-leader Steven Bensinger, VMD, PhD, at UCLA, is accomplished not through mutation, but by hijacking the signaling of a normal cell surface protein called platelet-derived growth factor receptor-beta or PDGFR-beta.
“It’s almost like a game of whack-a-mole,” said Mischel. “You use a drug to suppress a choice target and something else pops up to take its place and keep the cells alive—in this case a growth factor receptor that is perfectly normal in physiological terms.”
When scientists targeted both EGFR and PDGFR-beta in GBM tumors in animal models, the tumors were suppressed and drug resistance prevented. The next step is to develop clinical trials of treatments that target both involved proteins. And while this study focused on glioblastomas, Mischel and Bensinger believe the findings are relevant to other forms of cancer.
You can read the full Ludwig news release here.
University of California, San Diego Health System has been named among “100 Hospitals with Great Neurosurgery and Spine Programs” by Becker’s Hospital Review, a news publication for hospital and health system leadership.
According to the Becker’s Hospital Review editorial team, these hospitals offer outstanding spine and neurosurgical care, and were selected based on nominations, clinical accolades, quality care and other spine and neurosurgical proficiencies.
“The UC San Diego Neurological Institute is proud to have its neurosurgery program recognized as a leading program in complex brain and spine care,” said Bob Carter, MD, PhD, professor of surgery at UC San Diego School of Medicine, and chief of neurosurgery at UC San Diego Health System. “We have been fortunate to attract an outstanding cadre of neurosurgeons to UC San Diego who specialize in every form of neurosurgery, from minimally invasive techniques to the most complex spine and brain surgery.”
Taking down a tumor
Glioblastoma multiforme(GBM) is the most common and aggressive form of malignant brain tumor in humans. It has steadfastly defied efforts to treat it. Patients with GBMs either have an upfront resistance to current therapies or quickly develop one to the existing drug-based inhibitors designed to disable a protein called epidermal growth factor receptor or EGFR that is critical to tumor growth and survival.
As a result, a GBM prognosis is not good. Median survival time after diagnosis (usually made after the tumor is well-developed) is just 14 months.
In a paper published today in the Proceedings of the National Academy of Sciences, researchers from the Ludwig Institute for Cancer Research, UC San Diego, UCLA and the University of Sao Paolo in Brazil describe a mechanism in GBMs that defines its resistance to therapy. You can read the full news release here.
The work builds upon earlier research by Furnari and colleagues. Also, in 2011, UC San Diego scientists, in collaboration with colleagues in Boston and South Korea, identified a novel gene mutation that causes at least one form of GBM. Perhaps more importantly, the researchers found that two drugs already being used to treat other forms of cancer effectively prolonged the survival of mice modeling this particular form of the brain tumor.
Gene Mutations Cause Massive Brain Asymmetry
Discovery could help lead to prevention of radical surgery in rare childhood disease
Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.
In a paper published in the June 24, 2012 online issue of Nature Genetics, a team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.
De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings – a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues – suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.
Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analyzing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva.
“Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition,” said Gleeson. Realizing they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.
The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.