Mapping the Brain
Team advocates for noninvasive functional imaging
They are questions of curiosity. Thoughts on the intricate ways the human brain works and how each part works together to help us speak, let us move, give us memories. What happens when seizures disrupt brain activity and brain tumors grow? How does the mind adjust?
Finding answers meant everything for 17-year-old Grace Hugueley. After six years of ongoing seizures, her parents were afraid to leave her home alone. As doctors tried to control Grace’s generalized tonic-clonic seizures, her parents tracked her food consumption and activities. In all, they tried multiple seizure medications, cut caffeine from her diet and tried hormone regulation.
Grace was frustrated. “We couldn’t figure out what the common denominator was. At one point, I went three months without a seizure, and I was thinking, ‘Gosh, we finally figured it out.’ And then one hit me. That’s what frustrated me the most, I thought we figured it out and then we didn’t,” she said.
Grace didn’t want her parents to worry. One day, she wanted to go to college.
That’s what Andrew Papanicolaou, PhD, a pioneer in neuroimaging, wants for all children – for them to live at their highest potential. It’s why he studies the brain, using noninvasive brain mapping to understand structure and function.
As chief of Le Bonheur and the University of Tennessee Health Science Center’s (UTHSC) clinical neurosciences teams and co-director of Le Bonheur’s Neuroscience Institute, he and his colleagues have changed how brain mapping is used to make surgical decisions for children with epilepsy and brain tumors.
He’s finding hope for kids like Grace.
No “textbook case”
The goal is two-fold: find areas of the brain that are the cause of abnormal activity (seizures) and identify the areas nearby responsible for specific functions like speech and motor skills. “We know no two children’s brains are the same,” said James Wheless, MD, director of the epilepsy program and co-director of the Neuroscience Institute. “They may have similar-looking seizures. Imaging allows us to treat each child as an individual patient and have the best outcome for them. At the end of the day, that’s really what we want to do.”
Clinical neuroscientists tackle their search from both a structural and functional perspective. Modalities like MRI and CT take pictures of the brain structure while functional MRI (fMRI), magnetoencephalography (MEG) and transcranial magnetic stimulation (TMS) provide information about brain functions like language, memory and movement.
The clinical neurosciences team collaborates with neurologists, neurosurgeons, neuroradiologists and neuropsychologists to interpret information and guide surgical decisions. Noninvasive brain mapping gives families a much better idea of what life will be like post-surgery – whether physical therapy will be needed or if a patient will experience a weakness.
“The motivation of any researcher is to find out things. In this case, the intricate ways in which the brain works, sustains and mediates all the variety of functions that humans are capable of performing including memory, emotion, attention and so forth,” Papanicolaou said.
The intricate ways of the brain can get even more complicated for individuals with epilepsy or tumors, as normal pathways are disrupted. A brain will reorganize itself, and the area that controls a specific function will move. It can be unpredictable.
“If everything would stay put, you could read in the textbook where everything is, and the surgeon would not need this advanced information in order to maximize his surgical approach,” said Papanicolaou.
Questioning the gold standard
Direct cortical stimulation (done outside the operating room or in the operating room with an awake craniotomy) and Wada testing have been gold standards in evaluating function prior to tumor and lesion resection for decades.
With direct cortical stimulation, a neurosurgeon opens a patient’s skull, sedation is reduced and the patient is asked questions or to perform simple tasks. Responses help the surgeon know how to proceed. Still widely used across the country, the process is not ideal for children. With the Wada test, half of the brain is put to sleep using a medication (a barbiturate) while a patient’s ability to speak and respond is evaluated. Adolescent compliance is challenging and nearly impossible for younger children.
Le Bonheur’s clinical neurosciences team, after many documented cases, is advocating for an eventual replacement of the awake craniotomy and Wada test with noninvasive methods for most cases.1 MEG, TMS and fMRI together provide equally trustworthy results, the team believes.
A complete movement to only noninvasive brain mapping is still some years off, as very few centers have all of the technology and expertise to interpret results all under one roof.
“Tri-modality mapping and looking for concordance of the data between these three different techniques gives us belt and suspenders that we’re in the right location,” said Frederick Boop, MD, chairman of the Department of Neurosurgery for UTHSC and co-director of the Neuroscience Institute.
The adage “measure twice cut once” applies. Measuring with noninvasive testing twice, and in some cases three or four times, gives the team complete confidence in anatomical and functional location of the abnormalities.
While invasive methods, including grid placement, haven’t been eliminated at Le Bonheur, the team feels more and more confident in relying on noninvasive mapping when necessary. This is especially important for patients who have had previous surgeries or patients with significant developmental delay that would prohibit the use of grids.
“The more concordance we see between the invasive procedures that are considered the gold standards and the noninvasive approaches we emphasize here, the closer we may be in replacing the former with the latter,” said Roozbeh Rezaie, PhD, MEG lab director.
Shalini Narayana, MS, MBBS, PhD, runs the TMS lab and hopes one day, the complications from invasive mapping will no longer be barriers for patients.
“As you can imagine, there is no going back. Direct cortical stimulation is a one-time test. There are a lot of disadvantages to that – sedation, patient compliance, longer duration, more morbidity for the patient. When surgeons are armed with the information gathered from noninvasive mapping, they can actually tailor surgery to be more focal and less invasive. This can reduce the morbidity and lead to better outcomes,” she said.
The four-member clinical neurosciences team was recruited to Memphis to complement and support the growing neurology and neurosurgery program. Le Bonheur is home of one of the nation’s largest pediatric surgical brain tumor program2 in conjunction with St. Jude Children’s Research Hospital and a robust epilepsy program. The new members joined the hospital and the University of Tennessee Health Science Center in the last two and a half years – bringing with them clinical and research expertise in each of the modalities.
Papanicolaou has dedicated his career to the development of MEG, or magnetoencephalography. He wrote the very first textbook on the clinical applications of MEG and organized the International Society for the Advancement of Clinical Magnetoencephalography. He’s published dozens of papers on clinical MEG applications primarily about the localization of language networks in the brain.
In Memphis, he says he saw the opportunity to incorporate new developments in neuroimaging applications to pediatric neurosurgery and to collaborate with world-class clinical neuroscientists. And the team he’s recruited says that the technology, patient population and access to high-quality data open the door for discoveries.
Rezaie says the unique clinical cases and opportunities for research using all these modalities attracted him to the program.
“The success we have using these approaches is very rewarding and keeps you motivated to continue down this avenue, but also to try and develop new ideas from a research perspective. At some point in time, this research has the potential to make an impact clinically, with an emphasis on rapid turnarounds and improved outcomes for patients,” he said.
And it’s not just about the technology, it’s the team of experts working together who collaborate on every case.
“All of us work together,” said Asim Choudhri, MD, director of Neuroradiology. “We eat lunch together every day. We’re not different groups in different buildings that occasionally email each other. We work together every day because each patient is different. Each disease process is different. By not treating it in a cookie cutter manner, we can help patients and families understand, in their specific case, what they might expect after surgery.”
Efficiently mapping the brain
Because it works so closely, the clinical neurosciences team has also perfected efficiency in gathering functional information.
“Here, we can do all these tests in an afternoon, and the next morning, the surgeon has the information for the surgery. We’ve proven this and published case studies3 that show how efficient it can be when all the modalities are in close proximity and the people who operate them belong to the same group and collaborate,” said Papanicolaou.
Jennifer Barnes, 42, learned she had brain tumor – a rare oligodendroglioma – after experiencing a seizure while driving in 2007. At that time, her medical team felt the tumor wasn’t safe to resect because of its location, so her seizures were treated with medication. In 2013, the seizures couldn't be controlled any longer. Surgery was the best option.
Neurosurgeon Boop wanted to perform presurgical mapping and surgery to remove the tumor at Le Bonheur. While he has privileges at adult hospitals in the area, none was equipped to give him the precise information he needed to ensure Barnes that he could operate and minimize her risk for any deficits to her hand and facial motor and language functions.
“We entertained the idea of traveling to another city for treatment. My mother is an oncology nurse and she’s done tremendous research on my condition. She discovered that Le Bonheur’s on the cutting edge and has technology no one else has,” Barnes said.
So in one afternoon last July, Barnes underwent fMRI, MEG and TMS testing. The clinical neurosciences team, neuroradiologist, neurologist and neurosurgeon interpreted the results together and developed a plan to safely remove as much tumor as possible while minimizing the loss of function. Because of the complexity of the tumor, Jennifer had two surgeries – the first for subdural grid placement and the second for grid and tumor removal.
Using structural and functional images along with the results from grid placement, a three-dimensional model of Jennifer’s brain and the tumor was used to guide the surgery. Before leaving the operating room, Boop used scans by the intraoperative MRI (iMRI)4 to confirm that the maximum amount of tumor was resected while preserving eloquent cortex. See case study below.
Decisions made easier
In a perfect world, the clinical neurosciences team would hope to preserve all neurological function for its patients following surgery. But epilepsy and tumors can cause so much harm to a brain that it’s not possible.
“The truth is these patients are going to surgery for a reason. They’re having intractable seizures that are impairing their daily lives, impairing them going to school, impairing them from interacting appropriately with their family. They have tumors that could potentially take their life. So these are difficult decisions,” said Choudhri.
But thanks to noninvasive brain mapping, the conversations families are having before surgery have changed considerably in the last decade. Families have a better idea of what life could be like after surgery and what deficits may be possible. They can make a decision if life without seizures is worth those possible long-term deficits or short-term injuries.
“We are able to get information that we can go over with the family in a very calm manner, have a matter of fact discussion about what the information is telling us, and what the next steps are. It gives the family a chance to think about it, to discuss it with the surgeon,” said Wheless. “We are not doing it like we used to with the invasive electrodes. When we put these electrodes in, we’ve got to make a decision quickly because we have electrodes sitting in your child’s head, on their brain. Noninvasive mapping allows us to have the risk benefit discussion in a more relaxed manner with the family.”
When Grace Hugueley and her parents sat down to talk about surgery with Wheless and Boop, the teen was ready, but she had some questions. Would she still be the girl who loves to curl up in her dad’s lap? Would she be able to play the piano again?
The seizures originated from Grace’s left temporal lobe, the area that controls language and memory. The MRI appeared normal, so SPECT (single photon emission computed tomography) perfusion studies were used and detected an abnormality in the left temporal lobe. From there the concordance of data from fMRI, TMS, MEG and eventually subdural grid placement gave her team confidence that despite the normal MRI, they could perform a surgical resection of the area.
Since the surgery in July 2013, Grace hasn’t had one grand mal seizure, and medication minimizes the few brief focal seizures she’s experienced. Grace graduated from high school, got her learner’s permit to drive and will attend college this fall.
The sweetest part, her father Doug says, was hearing his daughter play “Clair de Lune” on the piano just days after the surgery. “
She didn’t miss a note,” he said.
1 Papanicolaou, A; Rezaie, R; Narayana, S; Choudhri, A; Wheless, J; Castillo, E; Baumgartner, J; Boop, F. Is it time to replace the Wada test and put awake craniotomy to sleep? Epilepsia 55 (5); 629-632, 2014.
2 Data source: Pediatric Health Information Systems (PHIS) Peer Hospitals ranked by U.S. News and World Report as Best Children’s Hospitals for Neurology & Neurosurgery, 2013.
3 Choudhri, A.; Narayana S., Rezaie, R.; Whitehead, M.; McAfee, S.; Wheless, J.; Boop, F.; Papanicolaou, A. Same Day Tri-Modality Functional Brain Mapping Prior to resection of a lesion involving the eloquent cortex: Technical feasibility. The Neuroradiology Journal 26: 548-554, 2013.
4 Choudhri, AF; Klimo, P; Auschwitz, TS; Whitehead, MT; Boop, FA. 3 Tesla intraoperative MRI for management of pediatric CNS neoplasms. American Journal of Neuroradiology 2014 (DOI: 10.3174/ajnr.A4040)