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The definitive version of this post was originally published on May 27, 2015 on the PLOS Neuroscience Community website, where I serve as an editor.
In 1861, the French scientific journal Bulletin de la Societe Anatomique published an article that would prove immeasurably important to the study of language and of the human brain . The article described M. Leborgne, a middle-aged patient who had suffered for the past 20 years from a striking inability to speak; so much so that he had become known as “Tan”, after the only syllable that he could utter. Leborgne had the misfortune to die soon afterwards, and the physician who had taken care of him in his last days performed an autopsy and collected the brain. What he found almost definitively established the notion of the cerebral localization of cognitive functions: Leborgne’s brain bore a single lesion in the inferior part of the left frontal lobe. Thus, focal and circumscribed brain damage was responsible for Leborgne’s loss of the ability to speak. The features of Leborgne’s speech impairment and the damaged area of his brain both came to bear the name of the physician who reported on his plight: Paul Broca.
The area and the syndrome do not match
Today, Broca’s area refers to the posterior portion of the inferior frontal gyrus on the left cerebral hemisphere, and Broca’s aphasia to an acquired alteration of spoken and written language that includes problems with speech fluency, word finding, repetition, and the ability to construct and understand grammatically complex sentences: patients suffering from Broca’s aphasia have a hard time getting words out and speak in short and hesitant sentences, sometimes called telegraphic speech. But the careful observation of numerous patients led many physicians and scientists to question the existence of an exclusive and absolute link between the two eponyms: there are patients whose Broca’s area is damaged, yet whose speech does not resemble that of Leborgne, and can even be almost normal; conversely, some patients speak like Leborgne after brain damage that does not involve the inferior frontal gyrus. How can one determine the precise role of Broca’s area given this discrepancy?
The rise of functional neuroimaging and neurophysiology affords another approach: rather than study patients whose brain is damaged or whose speech is abnormal, functional studies would measure the brain activity of healthy people while they speak. The question then becomes: what aspects of speech production—from conceptualizing a word to selecting its correct grammatical form to translating it into syllables to preparing the motor commands that would produce those syllables to finally executing the motor commands and speak—are under the control of Broca’s area? Unfortunately, technicalities got in the way: the phenomenon of speech production unfolds rather quickly in time, over a few hundreds of milliseconds, far beyond the temporal resolution of functional magnetic resonance imaging, which generally produces only about one “brain map” per second. On the other hand, several brain areas involved in speech production sit next to each other in the brain, which makes them impossible to resolve using electroencephalography and magnetoencephalography, despite the millisecond temporal resolution of those methods.
Probing the human brain’s function from within
If functional MRI is too slow and EEG is too blurry, would it mean that studying brain function during the production of normal speech is altogether impossible? Not quite: there are situations when medical conditions such as brain tumors or epilepsy dictate the placing of electrodes directly in contact with the human brain. These electrodes have the same millisecond temporal resolution as EEG, but with a spatial resolution and specificity that rivals that of functional MRI. In other words, they provide a uniquely detailed window onto the human brain’s functions. Neuroscientific research using intracranial electrodes is made possible thanks to the extraordinary generosity of the patients who agree to participate in extra tests and experiments despite the fact that they have just undergone a significant neurosurgical procedure.
In a study recently published in the Proceedings of the National Academy of Sciences, Dr. Adeen Flinker and colleagues, from the University of California, Berkeley and the Johns Hopkins University in Baltimore, used intracranial electrodes to reexamine the role of Broca’s area in speech production . They studied seven patients whose epilepsy could not be controlled by drugs and who were candidates for surgical removal of the epileptic focus in their brain. In these patients, the intracranial electrodes were necessary both to determine the exact origin of the seizures, and also to map cortical functions in order to spare areas essential for speech. Dr. Flinker asked the patients to repeat out loud words that they had just heard or read while he measured with millisecond precision neural activity in Broca’s area as well as in the motor cortex that ultimately controls the movements of the tongue and mouth, further back on the surface of the frontal lobe, and in parts of the temporal lobe important for hearing and the comprehension of language.
Resolving the role of Broca’s area with millisecond precision
When patients were repeating words that they had just heard or read, Dr. Flinker found a characteristic pattern of activation: first the auditory cortex, then Broca’s area, and finally the motor cortex. Importantly, activity in Broca’s area closely followed that in the auditory cortex, and by the time the patients were starting to speak themselves, neural activity in Broca’s area had resumed to its resting level. This suggests that Broca’s area cannot be responsible for actually coordinating speech movements. Flinker and colleagues then used Granger causality analysis, a statistical method originally developed in economic forecasting, in order to estimate the direction of information flow from one brain area to another. That analysis confirmed that the auditory cortex first influenced Broca’s area, which in turn influenced the motor cortex. Importantly, the influence of Broca’s area over the motor cortex had terminated before the patients started speaking. These results confirm that it could not be responsible for coordinating articulation.
In a clever twist built into the word repeating task, Flinker and colleagues included pseudo-words such as “yode” in addition to existing words such as “book”. The patients were able to speak these pseudo-words just as well as the standard ones, although it took them a little more time to do so. Crucially, Broca’s area was more intensely at work before the patients repeated the pseudo-words, suggesting that the role of that area was to prepare the novel articulatory combinations that were then executed in the motor cortex.
Flinker and colleagues’ findings nicely align with those of another study that directly assessed Broca’s area in different conditions: Dr. Matthew Tate and colleagues from the University Hospital of Montpellier, France, applied bursts of electrical stimulation directly to the surface of the cerebral cortex in patients who were undergoing neurosurgery  (I reported about that study here). Such a procedure, known as intraoperative mapping, sounds more painful and uncomfortable than it really is: after the patient’s brain has been exposed under general anesthesia, the patient is allowed to wake up on the operating table, with local anesthetics taking care of the pain caused by the surgery. She is then asked to repeat words, just as Dr. Flinker’s patients, while the neurosurgeon transiently and reversibly disrupts cortical function with electricity. Not your typical day in the park, but it is worth the effort: direct stimulation mapping yields the most precise functional maps of the human brain, and therefore ensures that the surgery won’t affect the patient’s language or cause any other disability. Dr. Tate and colleagues found that briefly tampering with Broca’s area while patients were speaking rarely prevented them from getting the words out altogether. Instead, it caused them to have “slips of the tongue”, paraphasias in technical parlance: incorrect wrong speech sounds would be inserted into words, but articulation would then proceed normally.
To scan a dead brain
If Broca’s area is not active during articulation itself, and if transiently impairing its function leaves patients able to articulate, why did Leborgne, and why do patients with Broca’s aphasia, have such massive difficulties to get any word out at all? Here, neuroimaging did make a critical contribution: Broca had the good idea of preserving Leborgne’s brain for posterity, which meant that it could be examined with a modern MRI scanner. That is just what Dr. Dronkers and colleagues, from the University of California, Davis and the Université Pierre et Marie Curie, Paris, did, and they found that the damage extended far beyond Broca’s area per se, also involving the neighboring parietal and temporal lobes, but especially reaching into the depth of the cerebral hemisphere and destroying most of the insula and part of the basal ganglia . In fairness to Broca, he did mention in his original report that the damage seemed more extensive than what he could see from the surface of the brain; but he chose not to dissect the brain precisely because he wanted to preserve it, and could therefore not assess the extent of the lesion completely. Thus, the apparent discrepancy between Broca’s area and Broca’s aphasia stems from the fact that the damage to Leborgne’s brain extended far beyond the confines of Broca’s area!
The story of Broca’s foundational discovery, and how modern neuroscience carefully refined and improved our understanding of the functional organization of speech production in the brain, is a vibrant example of cognitive neuroscience at work. There is no understating the absolutely crucial role of serendipitous clinical observations of patients with brain damage, the unfortunate victims of “Nature’s experiments”. Armed with modern neuroimaging and neurophysiological techniques, we can now functionally dissect the brain’s activity in health as well as in disease. The resulting, ever more detailed picture of the human brain at work changes the way we conceive of the relationship between our brains and our minds.
- Broca P. Remarques sur le siége de la faculté du langage articulé, suivies d’une observation d’aphémie (perte de la parole). Bull Soc Anat 1861;6:330–357.
- Flinker A, Korzeniewska A, Shestyuk AY, Franaszczuk PJ, Dronkers NF, Knight RT, & Crone NE (2015). Redefining the role of Broca’s area in speech. Proceedings of the National Academy of Sciences of the United States of America, 112 (9), 2871-5 PMID: 25730850
- Tate MC, Herbet G, Moritz-Gasser S, Tate JE, & Duffau H (2014). Probabilistic map of critical functional regions of the human cerebral cortex: Broca’s area revisited. Brain : a journal of neurology, 137 (Pt 10), 2773-82 PMID: 24970097
- Dronkers NF, Plaisant O, Iba-Zizen MT, & Cabanis EA (2007). Paul Broca’s historic cases: high resolution MR imaging of the brains of Leborgne and Lelong. Brain : a journal of neurology, 130 (Pt 5), 1432-41 PMID: 17405763
I’m introducing a new category of posts: short reviews of neuro-related books I recently read and liked (or didn’t!). I am starting this series with Michael Gazzaniga’s scientific autobiography, which was published earlier this year.
Michael S. Gazzaniga. Tales from both sides of the brain: a life in neuroscience. Ecco, 2015.
Why enjoyable? Because Dr. Gazzaniga is a great story-teller; in the book, his stories pleasantly weave together the essential (the inventiveness and drive that led Dr. Gazzaniga to build a neuropsychological testing laboratory, complete with an elaborate stimulus-presentation apparatus called tachistoscope, inside a trailer van in order to go test the patients at their homes) and the anecdotal (the joys of martinis at lunchtime in 1970’s Manhattan, or how to moonlight as a political meeting organizer while a grad student at Caltech).
Why legendary? Dr. Gazzaniga was instrumental in starting the field of cognitive neuroscience (he came up with the term itself) and founded both its Journal and its Society. His numerous studies brought essential insight into the human brain’s higher functions, perhaps most famously regarding the consequences of sectioning the interhemispheric commissures of the brain. Indeed, he was one of the major players in the ground-breaking work on split-brain patients that earned Dr. Roger W. Sperry the Nobel Prize in 1981.
What this book is not is a scientifically complete and concise, third-person summary of the research on split-brain patients; in that sense, I found the title slightly misleading. The subtitle is much more to the point: this is Dr. Gazzaniga’s “professional autobiography”, and we stand right behind him as he describes how his breath is taken away by the results of the first experiments that began to reveal hemispheric specialization in the human brain.
We literally stand right behind Dr. Gazzaniga, since he pioneered the archiving of neuropsychological tests on film. The book includes links to about two dozen movies that illustrate both the ingenuity of the experimental designs and the endlessly fascinating data yielded by split-brain patients.
Throughout the book, I was immensely impressed by Dr. Gazzaniga’s passion, his relentless energy in solving problems and coming up with solutions to help crack the secrets of cognitive function in the two halves of the brain. Despite not having learned as much about split-brain research as I had hoped to, I left the book reinvigorated with respect to my own scientific pursuits. I warmly recommend this book: some of Dr. Gannaziga’s enthusiasm for research is bound to rub off on his readers!
Here is my live-tweeting from this Special Interest Group session from the 2014 Annual Meeting of the American Epilepsy Society on Dec. 7 in Seattle, WA, collected on Storify.
This session in fact turned into one long presentation by Prof. Patrick Chauvel, from the CHU of Marseille. And it was a truly masterful lesson, with many fascinating video-intracranial EEG presentations of patients with epilepsy involving the prefrontal lobe. Dr. Chauvel drew anatomical-electrical-clinical correlates from each patient to build a systematic approach to these poorly understood epilepsies.
Here is my live-tweeting from this Investigators’ Workshop from the 2014 Annual Meeting of the American Epilepsy Society on Dec. 7 in Seattle, WA, collected in Storify.
Very interesting, thought-provoking session focusing in part on high-density micro-electrode array recordings of seizures in human patients (“Utah array”). The speakers were:
Here is my live-tweeting from this Investigators’ Workshop from the 2014 Annual Meeting of the American Epilepsy Society on Dec. 7 in Seattle, WA, collected in Storify.
This was a great session with many provocative ideas (starting with the title!), chaired by Dr. Jean Gotman from the Montreal Neurological Institute. The general discussion at the end of the presentations yielded several outstanding questions and exchanges between the panelists and the audience. The speakers were:
Here is my live-tweeting from this Special Interest Group session from the 2014 Annual Meeting of the American Epilepsy Society on Dec. 6 in Seattle, WA, collected in Storify.
These sessions, where very experimented clinicians and neurophysiologists discuss the relationships between the clinical features of seizures (semiology) and the brain areas involved in the seizure revealed by intracranial EEG, are extremely valuable to young clinicians and researchers interested in epilepsy and its neurophysiological underpinnings. The speakers for this session were:
Here is my live-tweeting from this Special Interest Group session from the 2014 Annual Meeting of the American Epilepsy Society on Dec. 5 in Seattle, WA, collected in Storify.
EEG source imaging is a particular forte of the group where I did my PhD, Christoph Michel’s Functional Brain Mapping Laboratory, at the University of Geneva Medical Faculty and Geneva University Hospitals, and of Margitta Seeck’s Epilepsy and EEG unit at Geneva University Hospitals where I trained in clinical neurophysiology and epileptology. I had a hugely rewarding feeling when some of the work I contributed to was presented at the session (first time ever for me)!
The speakers at the session were:
I have been extremely lucky this year to be able to attend both the Society for Neuroscience’s (#SfN14) and the American Epilepsy Society’s (#AESmtg14) annual meetings in close succession. And as I did for the SFN, I will be live-tweeting and blogging about the AES meeting over the next few days.
To get started, here is a Storify collection of my live-tweeting of the opening lecture, the Judith Hoyer lecture, given by Dr. Frances Jensen from the University of Pennsylvania. Dr. Jensen made the case for envisioning epilepsy as a spectrum disorder. In my opinion, it was the ideal way of opening the meeting, with insightful and thought-provoking ideas on how to broaden our vision of epilepsy research.
Stay tuned for more exciting research on epilepsy, its neural underpinnings, its consequences and its therapies from #AESmtg14!
303.Poster session. Oscillations: EEG.
Monday, Nov 17, 2014, 8 AM-12 PM.
I really enjoy poster sessions and the unique opportunities for interacting with the authors that they offer. This morning, I spent some time at the session on brain oscillations as studied by EEG. Here are highlights from a couple of posters (three, actually) that I had the opportunity to discuss with their authors. My apologies to the presenters whose posters I did not cover. Note that any inaccuracy or outright misunderstanding in what follows is my responsibility alone!
303.03/C39. Phase dependency of long-range neuronal transmission in entrained neuronal networks: A combined tACS-TMS-EEG study. K. D. FEHÉR, Y. MORISHIMA.
303.05/C41. A method for removing tACS artifacts from EEG data. Y. MORISHIMA, K. D. FEHÉR.
The authors of these posters, from the University of Bern, Switzerland, have combined seemingly for the first time transcranial alternating current stimulation (tACS), a noninvasive approach to modulate brain rhythms, together with transcranial magnetic stimulation (TMS), which allows sending brief, sudden pulses of simulation to the cortex, and EEG recordings.
First of all, they had to find a way of removing the tACS artifact that was orders of magnitude larger than the actual brain signals in the EEG (poster C41). Their approach involved upsampling of the EEG signals so that the EEG sampling rate was a multiple of the tACS frequency, trigger timing adjustment , then moving-window average filter, and finally PCA. Using that method, the authors were able to retrieve clean EEG and visual evoked potentials.
The authors then investigated how the phase of ongoing brain oscillations, here imposed by the tACS (6 Hz delivered to both frontal and parietal areas using 2 stimulators), influenced brain responses to sudden, punctual stimulation delivered by TMS (poster C39). They found widespread dependence of TMS-evoked potentials on the phase of tACS when both frontal and partial cortex were stimulated in phase. Interestingly, effects were restricted to the posterior electrodes when the phases of stimulation of frontal and parietal cortex were opposed.
Their preliminary results confirm the importance of ongoing brain oscillations in modulating brain responses. The next steps according to the authors will include testing other frequencies of tACS, such as the gamma band.
303.23/C59. An automated seizure onset zone detector using high frequency oscillations. S. GLISKE, W. C. STACEY.
The authors of this poster, from the University of Michigan, were interested in high-frequency oscillations (HFOs), brief periods of oscillatory activity (generally between 80 and 200 Hz) recorded by intracranial EEG in patients suffering from severe epilepsy. It is thought that HFOs are a specific marker of the seizure onset zone (SOZ), the part of the brain where seizures originate from and that should be removed surgically to cure the patients from their epilepsy.
HFOs are hard to detect “visually” by browsing the EEG; therefore, algorithms to detect HFOs have been developed, but perform poorly because there are many “false” detections. The authors therefore developed a series of algorithms that would detect and label those artifacts, avoiding false positives. They tested their algorithm in clinically annotated intracranial EEG recordings from the intracranial EEG portal, a data-sharing initiative (ieeg.org), as well as in data from patients at their local institution.
They found that their automated algorithm detected localized HFOs in just over half of the patients (53%). In all those cases, the HFOs were included either in the SOZ, as labeled by expert clinicians, or in the surgically resected area. These two zones are collectively considered the gold standard for localizing the source of seizures in epilepsy surgery. Importantly, although the current study was retrospective, the algorithm is fast enough that it can be run in real-time as data are collected.
In conclusion, the authors presented a specific, albeit not very sensitive, approach to localizing the seizure onset zone using an automated high-frequency oscillation detector. The next steps according to the authors will include investigating whether HFO detection influences clinical decision making. The possibility to perform data analysis online will prove crucial in that respect.