CNL’s unique capabilities of probing single neuron activity in awake patients who can declare their experiences and memories have resulted in a string of discoveries including the discovery of Place Cells (Nature, 2003), Grid-like Cells (Nature Neuroscience, 2013; Current Biology, 2014), Path Cells (PNAS 2010), auditory cortex cells with exquisite pitch discrimination (Nature, 2008), Imagery Neurons (Nature, 2000), and Concepts Cells (Nature, 2005; Scientific American, 2013). Persistent specific neuronal activity was found during the experience and spontaneous recall or imagery of the experience (Science 2008). The short and long term assimilation and maintenance of associations in human memory was also demonstrated at the single neuron level (Neuron, 2015, Nature Communications, 2016).
Since the original report by Fried et al. (1991) on the somatotopic organization of the supplementary motor area (SMA) and the elicitation of human urge by stimulation there, CNL has been active in probing the underlying neuronal mechanisms of intention and action in the human mesial frontal area. The capability of probe single neuron activity when subjects could declare their intentions and urges provided extraordinary opportunity to show the gradual recruitment and increased activity in single neurons in the SMA, preSMA and anterior cingulate cortex before conscious recognition of the will to act (Neuron, 2011). In 2010 we reported the existence of mirror neurons in the human brain, both in mesial frontal and mesiotemporal regions (Current Biology, 2010).
The setting of neurosurgery offers a unique opportunity to modulate brain function in distinct clinical settings. In 2010 CNL reported on a brain-machine interface composed of four neurons who activity was voluntarily modulated by patients to “project” an image, a “thought”, on a screen (Nature 2010). Dr. Fried has used electrical stimulation extensively during brain surgery under local anesthesia to provide individual maps of brain organization that would guide the extent and limits of brain resection. At the same time the reports by patients when brain centers were stimulated provided rare insight into cognitive functions and the extent to which electrical stimulation could modify them. Such functions included laughter (Nature, 1998), music, and intentions. More recently stimulation of the entorhinal region was shown by CNL investigators to enhance subsequent memory performance. (New England Journal of Medicine, 2012, Neuroimage, 2014, Brain 2015). Currently we collaborate with our neuroengineering colleagues to build a neuroprosthetic device- a Memory Aid-that will provide the minimally invasive closed loop requirement for detailed recordings and stimulation in the mesial temporal lobe.
CNL has the capability to record simultaneously scalp EEG, intracerebral EEG, and unit firing in multiple brain regions of neurosurgical patients during sleep. We find that most sleep slow waves and the underlying active and inactive neuronal states occur locally. Thus, especially in late sleep, some regions can be active while others are silent. We also find that slow waves can propagate, usually from medial prefrontal cortex to the medial temporal lobe and hippocampus. Sleep spindles, the other hallmark of NREM sleep EEG, are likewise predominantly local. Thus, intracerebral communication during sleep is constrained because slow and spindle oscillations often occur out-of-phase in different brain regions (Neuron, 2011).
Examining eye movements during sleep we find that that rapid eye movements during sleep rearrange discrete epochs of visual-like processing as during wakefulness (Nature Communication, 2015).
Epilepsy is a neurological disorder affecting 1-2% of the population. A third of these patients have seizures which cannot be controlled by drugs and many of these can be helped by brain surgery. UCLA epilepsy surgery program is one of the world premier program and offers a wide spectrum of surgical procedures from resection of epileptogenic foci to disconnection procedures and procedures involving brain stimulation to avert seizures. UCLA has led a major multicenter study showing the benefits of early surgery for temporal lobe epilepsy (JAMA, 2012). UCLA epilepsy surgery program has been at the forefront of the study of basic mechanisms of epilepsy. Using depth electrodes implanted in neurosurgical epilepsy patients the UCLA group has been first to demonstrate the role of high frequency oscillations (HFOs) in epileptogenesis
Some of the cutting edge technologies used by the UCLA Epilepsy Surgery program include MRI-guided laser ablation of epileptogenic brain foci achieved by a tiny incision and insertion of a delicate laser fiber into the brain, as well as the recently FDA-approved Responsive Neurostimulator (RNS) by Neuropace which acts like a cardiac defibrillator and provides stimulation guided by recording of the brain activity at the onset of a seizure.
At he same time epilepsy surgery provides a window into brain mechanisms and the human mind. Some patients need insertion of delicate electrodes into the brain to localize the brain network responsible for the seizures. These patients are monitored in the hospital for 1-2 weeks until sufficient number of seizures are recorded. This extraordinary clinical setting enables recording of single neuron activity associated with a variety of cognitive functions.
In 1998 Dr. Fried has founded an epilepsy surgery program in Israel, the first of its kind in the region. It was modelled after the UCLA epilepsy surgery program and started at the Tel-Aviv Sourasky Medical Center affiliated with Tel-Aviv University. The center now performs most of the epilepsy surgery in Israel on pediatric and adult patients, and employs a variety of procedures including hemispherotomy, anteromedial temporal lobectomy, resection of various lesions, implantation of subdural and depth electrodes, Vagal nerve stimulation and deep brain stimulation. In collaboration with scientists in the Weizmann Institute, Tel-Aviv University, the Hebrew University in Jerusalem and the Technion in Haifa, various research projects have been carried out, partly funded by the Israeli Science Foundation and the Binational Israel-US Science Foundation. Part of this research was funded through a special Center for Excellence for Cognitive Sciences (I-CORE).
Syndrome E is not directly related to Dr. Fried’s neurophysiological research. It is a distinct hypothesis that he originally proposed in an article in the Lancet (Fried, 1997)
The transformation of groups of previously nonviolent individuals into repetitive killers of defenseless members of society has been a recurring phenomenon throughout history. This apparent transition of large numbers of seemingly normal, “ordinary” individuals, to perpetrators of extreme atrocities is one of the most striking variants of human behavior, but often appear incomprehensible to victims and bystanders and in retrospect even to the perpetrators themselves and to society in general.
This transition is characterized by a set of symptoms and signs for which a common syndrome has been proposed, Syndrome E (Fried, Lancet, 1997). A pathophysiological model — “cognitive fracture” — was hypothesized, positing that the syndrome is a product of neocortical development rather than the manifestation of a disinhibited primitive brain. The purpose of designating such a phenomenon as a syndrome is not to medicalize this form of human behavior, but to provide a framework for future discussion and multidisciplinary discourse and for potential insights that might lead to early detection and prevention.
In 2015 and 2016 two conferences were convened by Dr. Fried – “The Brains that Pull the Triggers” which take place under the auspices of the Paris Institute for Advanced Studies at the magnificent Hotel de Lauzun in Paris. This conferences brought together scientists and scholars from the human, social and brain sciences as well as legal scholars. These conferences were reviewed in a special editorial (The Kill Switch) by Nature, as well as in an article in The New Scientist.
