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1.  Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy 
JAMA  2012;307(9):922-930.
Context
Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death.
Objective
We sought to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL).
Design, Setting, and Participants
The Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged ≥ 12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizues for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003–2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual.
Intervention
Receipt of continued AED treatment (n=23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery.
Main Outcome Measures
The primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89] overall T-score), cognitive function, and social adaptation.
Results
Zero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (odds ratio=∞; 95% CI, 11.8 to ∞;P <.001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was higher in the surgical group than in the medical group but this difference was not statistically significant (12.6 vs 4.0 points; treatment effect = 8.5; 95% CI, −1.0 to 18.1; P =.08). When data obtained after surgery from participants in the medical group were excluded, the effect of surgery on QOL was significant (12.8 vs 2.8 points; treatment effect=9.9; 95% CI, 2.2 to 17.7; P =.01). Memory decline (assessed using the Rey Auditory Verbal Learning Test) occurred in 4 participants (36%) after surgery, consistent with rates seen in the literature; but the sample was too small to permit definitive conclusions about treatment group differences in cognitive outcomes. Adverse events included a transient neurologic deficit attributed to a magnetic resonance imaging–identified postoperative stroke in a participant who had surgery and 3 cases of status epilepticus in the medical group.
Conclusions
Among patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone. Given the premature termination of the trial, the results should be interpreted with appropriate caution.
doi:10.1001/jama.2012.220
PMCID: PMC4821633  PMID: 22396514
2.  New approaches to structural and functional imaging in focal epilepsy 
Epilepsia  2010;51(Suppl 1):83-86.
doi:10.1111/j.1528-1167.2009.02456.x
PMCID: PMC4801111  PMID: 20331726
3.  Rapid Encoding of New Memories by Individual Neurons in the Human Brain 
Neuron  2015;87(1):220-230.
Summary
The creation of memories about real-life episodes requires rapid neuronal changes that may appear after a single occurrence of an event. How is such demand met by neurons in the medial temporal lobe (MTL), which plays a fundamental role in episodic memory formation? We recorded the activity of MTL neurons in neurosurgical patients while they learned new associations. Pairs of unrelated pictures, one of a person and another of a place, were used to construct a meaningful association modeling the episodic memory of meeting a person in a particular place. We found that a large proportion of responsive MTL neurons expanded their selectivity to encode these specific associations within a few trials: cells initially responsive to one picture started firing to the associated one but not to others. Our results provide a plausible neural substrate for the inception of associations, which are crucial for the formation of episodic memories.
Highlights
•Contextual associations were used to model the formation of new memories•Human single neurons changed their firing patterns to encode new associations•Changes occurred at the exact moment of learning, even after single presentations•The rapid speed of neural changes is compatible with episodic memory formation
Ison et al. recorded from single neurons in the human brain while patients learned contextual associations. They found that neurons change their firing to incept new associations even after one single presentation, thus providing a plausible mechanism underlying memory formation.
doi:10.1016/j.neuron.2015.06.016
PMCID: PMC4509714  PMID: 26139375
4.  Deep Brain Stimulation for Enhancement of Learning and Memory 
NeuroImage  2013;85(0 3):996-1002.
doi:10.1016/j.neuroimage.2013.07.066
PMCID: PMC4445933  PMID: 23921099
5.  Structured neuronal encoding and decoding of human speech features 
Nature communications  2012;3:1015.
Human speech sounds are produced through a coordinated movement of structures along the vocal tract. Here we show highly structured neuronal encoding of vowel articulation. In medial-frontal neurons, we observe highly specific tuning to individual vowels, whereas superior temporal gyrus neurons have non-specific, sinusoidally-modulated tuning (analogous to motor cortical directional tuning). At the neuronal population level, a decoding analysis reveals that the underlying structure of vowel encoding reflects the anatomical basis of articulatory movements. This structured encoding enables accurate decoding of volitional speech segments and could be applied in the development of Brain-Machine Interfaces for restoring speech in paralyzed individuals.
doi:10.1038/ncomms1995
PMCID: PMC4445934  PMID: 22910361
6.  Limbic Neuromodulation 
doi:10.1016/j.nec.2013.08.004
PMCID: PMC4445935  PMID: 24262905
Deep brain stimulation; Addiction; Dementia; Memory; Posttraumatic stress disorder; Alzheimer; Limbic system
7.  Sparse decoding of multiple spike trains for brain-machine interfaces 
Journal of neural engineering  2012;9(5):054001.
Brain-machine interfaces (BMIs) rely on decoding neuronal activity from a large number of electrodes. The implantation procedures, however, do not guarantee that all recorded units encode task-relevant information: selection of task-relevant neurons is critical to performance but is typically performed heuristically. Here, we describe an algorithm for decoding/classification of volitional actions from multiple spike trains, which automatically selects the relevant neurons. The method is based on sparse decomposition of the high-dimensional neuronal feature space, projecting it onto a low-dimensional space of codes serving as unique class labels. The new method is tested against a range of existing methods using simulations and recordings of the activity of 1592 neurons in 23 neurosurgical patients who performed motor or speech tasks. The parameter estimation algorithm is orders of magnitude faster than existing methods, and achieves significantly higher accuracies for both simulations and human data, rendering sparse decomposition highly attractive for BMIs.
doi:10.1088/1741-2560/9/5/054001
PMCID: PMC4445936  PMID: 22954906
8.  Cognitive-motor brain–machine interfaces 
Journal of physiology, Paris  2013;108(1):38-44.
Brain–machine interfaces (BMIs) open new horizons for the treatment of paralyzed persons, giving hope for the artificial restoration of lost physiological functions. Whereas BMI development has mainly focused on motor rehabilitation, recent studies have suggested that higher cognitive functions can also be deciphered from brain activity, bypassing low level planning and execution functions, and replacing them by computer-controlled effectors. This review describes the new generation of cognitive-motor BMIs, focusing on three BMI types: Speech BMI – reconstructing a person’s speech based on the neuronal activity.Direct object control – controlling object movement without mimicking the limb movement that would yield the desired object movement.Decoding internal processes, such as neuronal representations of sensory information and decision making.
By outlining recent progress in developing these BMI types, we aim to provide a unified view of contemporary research towards the replacement of behavioral outputs of cognitive processes by direct interaction with the brain.
doi:10.1016/j.jphysparis.2013.05.005
PMCID: PMC4424044  PMID: 23774120
Brain–machine interface; Speech; Direct object control; Decision making; Percept decoding; Human neurophysiology
9.  Ictal Depth EEG and MRI Structural Evidence for Two Different Epileptogenic Networks in Mesial Temporal Lobe Epilepsy 
PLoS ONE  2015;10(4):e0123588.
Hypersynchronous (HYP) and low voltage fast (LVF) activity are two separate ictal depth EEG onsets patterns often recorded in presurgical patients with MTLE. Evidence suggests the mechanisms generating HYP and LVF onset seizures are distinct, including differential involvement of hippocampal and extra-hippocampal sites. Yet the extent of extra-hippocampal structural alterations, which could support these two common seizures, is not known. In the current study, preoperative MRI from 24 patients with HYP or LVF onset seizures were analyzed to determine changes in cortical thickness and relate structural changes to spatiotemporal properties of the ictal EEG. Overall, onset and initial ipsilateral spread of HYP onset seizures involved mesial temporal structures, whereas LVF onset seizures involved mesial and lateral temporal as well as orbitofrontal cortex. MRI analysis found reduced cortical thickness correlated with longer duration of epilepsy. However, in patients with HYP onsets, the most affected areas were on the medial surface of each hemisphere, including parahippocampal regions and cingulate gyrus, whereas in patients with LVF onsets, the lateral surface of the anterior temporal lobe and orbitofrontal cortex showed the greatest effect. Most patients with HYP onset seizures were seizure-free after resective surgery, while a higher proportion of patients with LVF onset seizures had only worthwhile improvement. Our findings confirm the view that recurrent seizures cause progressive changes in cortical thickness, and provide information concerning the structural basis of two different epileptogenic networks responsible for MTLE. One, identified by HYP ictal onsets, chiefly involves hippocampus and is associated with excellent outcome after standardized anteromedial temporal resection, while the other also involves lateral temporal and orbitofrontal cortex and a seizure-free surgical outcome occurs less after this procedure. These results suggest that a more extensive tailored resection may be required for patients with the second type of MTLE.
doi:10.1371/journal.pone.0123588
PMCID: PMC4388829  PMID: 25849340
10.  Single-Cell Responses to Face Adaptation in the Human Medial Temporal Lobe 
Neuron  2014;84(2):363-369.
Summary
We used a face adaptation paradigm to bias the perception of ambiguous images of faces and study how single neurons in the human medial temporal lobe (MTL) respond to the same images eliciting different percepts. The ambiguous images were morphs between the faces of two familiar individuals, chosen because at least one MTL neuron responded selectively to one but not to the other face. We found that the firing of MTL neurons closely followed the subjects’ perceptual decisions—i.e., recognizing one person or the other. In most cases, the response to the ambiguous images was similar to the one obtained when showing the pictures without morphing. Altogether, these results show that many neurons in the medial temporal lobe signal the subjects’ perceptual decisions rather than the visual features of the stimulus.
Highlights
•We used a face adaptation paradigm to bias the perception of ambiguous images•Neurons in the human MTL fired according to the subjects’ perceptual decisions•In most cases, ambiguous images triggered similar responses as the original pictures•MTL neurons follow subjective perception rather than visual inputs
Using an adaptation paradigm to bias the perception of morphed faces, Quian Quiroga et al. show how single neurons in the human medial temporal lobe follow the subjective perception by the subjects rather than the visual features of the stimulus.
doi:10.1016/j.neuron.2014.09.006
PMCID: PMC4210637  PMID: 25263754
11.  Coding of Information in the Phase of Local Field Potentials within Human Medial Temporal Lobe 
Neuron  2013;79(3):10.1016/j.neuron.2013.06.001.
Summary
There is increasing evidence that the phase of ongoing oscillations plays a role in neural coding, but its relative importance throughout the brain has yet to be understood. We assessed single-trial phase coding in four temporal lobe and four frontal lobe regions of the human brain using local field potentials (LFPs) recorded during a card-matching task. In the temporal lobe, classification of correct/incorrect matches based on LFP phase was significantly better than classification based on amplitude and comparable to the full LFP signal. Surprisingly, in these regions, the correct/incorrect mean phases became aligned to one another before they diverged and coded for trial outcome. Neural responses in the amygdala were consistent with a mechanism of phase resetting, while parahippocampal gyrus activity was indicative of evoked potentials. These findings highlight the importance of phase coding in human MTL and suggest that different brain regions may represent information in diverse ways.
doi:10.1016/j.neuron.2013.06.001
PMCID: PMC3835725  PMID: 23932002
12.  Timing of Single-Neuron and Local Field Potential Responses in the Human Medial Temporal Lobe 
Current biology : CB  2014;24(3):299-304.
Summary
The relationship between the firing of single cells and local field potentials (LFPs) has received increasing attention, with studies in animals [1-11] and humans [12-14]. Recordings in the human medial temporal lobe (MTL) have demonstrated the existence of neurons with selective and invariant responses [15], with a relatively late but precise response onset around 300 ms after stimulus presentation [16-18] and firing only upon conscious recognition of the stimulus [19]. This represents a much later onset than expected from direct projections from inferotemporal cortex [16, 18]. The neural mechanisms underlying this onset remain unclear. To address this issue, we performed a joint analysis of single-cell and LFP responses during a visual recognition task. Single-neuron responses were preceded by a global LFP deflection in the theta range. In addition, there was a local and stimulus-specific increase in the single-trial gamma power. These LFP responses correlated with conscious recognition. The timing of the neurons’ firing was phase locked to these LFP responses. We propose that whereas the gamma phase locking reflects the activation of local networks encoding particular recognized stimuli, the theta phase locking reflects a global activation that provides a temporal window for processing consciously perceived stimuli in the MTL.
doi:10.1016/j.cub.2013.12.004
PMCID: PMC3963414  PMID: 24462002
13.  Direct recordings of grid-like neuronal activity in human spatial navigation 
Nature neuroscience  2013;16(9):1188-1190.
Grid cells in the entorhinal cortex appear to represent spatial location via a triangular coordinate system. Such cells, which have been identified in rats, bats, and monkeys, are believed to support a wide range of spatial behaviors. By recording neuronal activity from neurosurgical patients performing a virtual-navigation task we identified cells exhibiting grid-like spiking patterns in the human brain, suggesting that humans and simpler animals rely on homologous spatial-coding schemes.
doi:10.1038/nn.3466
PMCID: PMC3767317  PMID: 23912946
14.  Timing of Single-Neuron and Local Field Potential Responses in the Human Medial Temporal Lobe 
Current Biology  2014;24(3):299-304.
Summary
The relationship between the firing of single cells and local field potentials (LFPs) has received increasing attention, with studies in animals [1–11] and humans [12–14]. Recordings in the human medial temporal lobe (MTL) have demonstrated the existence of neurons with selective and invariant responses [15], with a relatively late but precise response onset around 300 ms after stimulus presentation [16–18] and firing only upon conscious recognition of the stimulus [19]. This represents a much later onset than expected from direct projections from inferotemporal cortex [16, 18]. The neural mechanisms underlying this onset remain unclear. To address this issue, we performed a joint analysis of single-cell and LFP responses during a visual recognition task. Single-neuron responses were preceded by a global LFP deflection in the theta range. In addition, there was a local and stimulus-specific increase in the single-trial gamma power. These LFP responses correlated with conscious recognition. The timing of the neurons’ firing was phase locked to these LFP responses. We propose that whereas the gamma phase locking reflects the activation of local networks encoding particular recognized stimuli, the theta phase locking reflects a global activation that provides a temporal window for processing consciously perceived stimuli in the MTL.
Highlights
•Global theta LFP increases immediately precede MTL single-cell responses•Gamma power reflects activations of local networks encoding specific stimuli•The timing of the neurons’ firing is phase locked to LFP responses•LFP responses give a temporal window for processing consciously perceived stimuli
Rey et al. show that, in human medial temporal lobe (MTL), single-cell responses triggered by consciously perceived stimuli are locked to global theta and local gamma LFP responses; the latter reflects local activations, but the former shortly precedes the spike responses and may provide a window for stimulus processing in the MTL.
doi:10.1016/j.cub.2013.12.004
PMCID: PMC3963414  PMID: 24462002
15.  Human hypocretin and melanin concentrating hormone levels are linked to emotion and social interaction 
Nature communications  2013;4:1547.
The neurochemical changes underlying human emotions and social behavior are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 (Hcrt-1) and melanin concentrating hormone (MCH), measured in the human amygdala. We show that Hcrt-1 levels are maximal during positive emotion, social interaction, and anger, behaviors that induce cataplexy in human narcoleptics. In contrast, MCH levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. MCH levels increase at sleep onset, consistent with a role in sleep induction, whereas Hcrt-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized.
doi:10.1038/ncomms2461
PMCID: PMC3595130  PMID: 23462990
16.  Ensembles of human MTL neurons “jump back in time” in response to a repeated stimulus 
Hippocampus  2012;22(9):1833-1847.
Episodic memory, which depends critically on the integrity of the medial temporal lobe (MTL), has been described as “mental time travel” in which the rememberer “jumps back in time.” The neural mechanism underlying this ability remains elusive. Mathematical and computational models of performance in episodic memory tasks provide a specific hypothesis regarding the computation that supports such a jump back in time. The models suggest that a representation of temporal context, a representation that changes gradually over macroscopic periods of time, is the cue for episodic recall. According to these models, a jump back in time corresponds to a stimulus recovering a prior state of temporal context. In vivo single-neuron recordings were taken from the human MTL while epilepsy patients distinguished novel from repeated images in a continuous recognition memory task. The firing pattern of the ensemble of MTL neurons showed robust temporal autocorrelation over macroscopic periods of time during performance of the memory task. The gradually-changing part of the ensemble state was causally affected by the visual stimulus being presented. Critically, repetition of a stimulus caused the ensemble to elicit a pattern of activity that resembled the pattern of activity present before the initial presentation of the stimulus. These findings confirm a direct prediction of this class of temporal context models and may be a signature of the mechanism that underlies the experience of episodic memory as mental time travel.
doi:10.1002/hipo.22018
PMCID: PMC3407826  PMID: 22488671
17.  Improved P300 speller performance using electrocorticography, spectral features, and natural language processing 
Objective
The P300 speller is a system designed to restore communication to patients with advanced neuromuscular disorders. This study was designed to explore the potential improvement from using electrocorticography (ECoG) compared to the more traditional usage of electroencephalography (EEG).
Methods
We tested the P300 speller on two epilepsy patients with temporary subdural electrode arrays over the occipital and temporal lobes respectively. We then performed offline analysis to determine the accuracy and bit rate of the system and integrated spectral features into the classifier and used a natural language processing (NLP) algorithm to further improve the results.
Results
The subject with the occipital grid achieved an accuracy of 82.77% and a bit rate of 41.02, which improved to 96.31% and 49.47 respectively using a language model and spectral features. The temporal grid patient achieved an accuracy of 59.03% and a bit rate of 18.26 with an improvement to 75.81% and 27.05 respectively using a language model and spectral features. Spatial analysis of the individual electrodes showed best performance using signals generated and recorded near the occipital pole.
Conclusions
Using ECoG and integrating language information and spectral features can improve the bit rate of a P300 speller system. This improvement is sensitive to the electrode placement and likely depends on visually evoked potentials.
Significance
This study shows that there can be an improvement in BCI performance when using ECoG, but that it is sensitive to the electrode location.
doi:10.1016/j.clinph.2013.02.002
PMCID: PMC3679217  PMID: 23465430
brain-computer interface; electrocorticography; event-related potential; P300; speller; natural language processing
18.  Contrasting Roles of Neural Firing Rate and Local Field Potentials in Human Memory 
Hippocampus  2007;17(8):606-617.
Recording the activity of neurons is a mainstay of animal memory research, while human recordings are generally limited to the activity of large ensembles of cells. The relationship between ensemble activity and neural firing rate during declarative memory processes, however, remains unclear. We recorded neurons and local field potentials (LFPs) simultaneously from the same sites in the human hippocampus and entorhinal cortex (ERC) in patients with implanted intracranial electrodes during a virtual taxi-driver task that also included a memory retrieval component. Neurons increased their firing rate in response to specific passengers or landmarks both during navigation and retrieval. Although we did not find item specificity in the broadband LFP, both θ- and γ-band LFPs increased power to specific items on a small but significant percent of channels. These responses, however, did not correlate with item-specific neural responses. To contrast item-specific responses with process-specific responses during memory, we compared neural and LFP responses during encoding (navigation) and retrieval (associative and item-specific recognition). A subset of neurons also altered firing rates nonspecifically while subjects viewed items during encoding. Interestingly, LFPs in the hippocampus and ERC increased in power nonspecifically while subjects viewed items during retrieval, more often during associative than item-recognition. Furthermore, we found no correlation between neural firing rate and broadband, θ-band, and γ-band LFPs during process-specific responses. Our findings suggest that neuronal firing and ensemble activity can be dissociated during encoding, item-maintenance, and retrieval in the human hippocampal area, likely relating to functional properties unique to this region.
doi:10.1002/hipo.20300
PMCID: PMC3568989  PMID: 17546683
hippocampus; depth electrode; local field potentials; single neuron; human memory; declarative memory
19.  Gray matter loss correlates with mesial temporal lobe neuronal hyperexcitability inside the human seizure onset zone 
Epilepsia  2011;53(1):25-34.
Summary
Purpose
Patient studies have not provided consistent evidence for interictal neuronal hyperexcitability inside the seizure onset zone (SOZ). We hypothesized that gray matter (GM) loss could have important effects on neuronal firing, and quantifying these effects would reveal significant differences in neuronal firing inside versus outside the SOZ.
Methods
MRI and computational unfolding of mesial temporal lobe (MTL) subregions was used to construct anatomical maps to compute GM loss in presurgical patients with medically intractable focal seizures in relation to control subjects. In patients, these same maps were used to locate the position of microelectrodes that recorded interictal neuronal activity. Single neuron firing and burst rates were evaluated in relation to GM loss and MTL subregions inside and outside the SOZ.
Key findings
MTL GM thickness was reduced inside and outside the SOZ in patients with respect to control subjects, yet GM loss was associated more strongly with firing and burst rates in several MTL subregions inside the SOZ. Adjusting single neuron firing and burst rates for the effects of GM loss revealed significantly higher firing rates in the subregion consisting of dentate gyrus and CA2 and CA3 (CA23DG), as well as CA1 and entorhinal cortex (EC) inside versus outside the SOZ where normalized MRI GM loss was ≥1.40 mm. Firing rates were higher in subicular cortex inside the SOZ at GM loss ≥1.97 mm, while burst rates were higher in CA23DG, CA1, and EC inside than outside the SOZ at similar levels of GM loss.
Significance
The correlation between GM loss and increased firing and burst rates suggests GM structural alterations in MTL subregions are associated with interictal neuronal hyperexcitability inside the SOZ. Significant differences in firing rates and bursting in areas with GM loss inside compared to outside the SOZ indicate that synaptic reorganization following cell loss could be associated with varying degrees of epileptogenicity in patients with intractable focal seizures.
doi:10.1111/j.1528-1167.2011.03333.x
PMCID: PMC3253228  PMID: 22126325
epilepsy; atrophy; interictal; hippocampus; MRI; microelectrode; single neuron
20.  A category-specific response to animals in the right human amygdala 
Nature neuroscience  2011;14(10):1247-1249.
The amygdala is important in emotion, but it remains unknown whether it is specialized for certain stimulus categories. We analyzed responses recorded from 489 single neurons in the amygdalae of 41 neurosurgical patients and found a categorical selectivity for pictures of animals in the right amygdala. This selectivity appeared to be independent of emotional valence or arousal and may reflect the importance that animals held throughout our evolutionary past.
doi:10.1038/nn.2899
PMCID: PMC3505687  PMID: 21874014
21.  Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area 
The New England journal of medicine  2012;366(6):502-510.
BACKGROUND
The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.
METHODS
We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus).
RESULTS
Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.
CONCLUSIONS
Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.)
doi:10.1056/NEJMoa1107212
PMCID: PMC3447081  PMID: 22316444
22.  Sleep spindles in humans: insights from intracranial EEG and unit recordings 
The Journal of Neuroscience  2011;31(49):17821-17834.
Sleep spindles are an electroencephalographic (EEG) hallmark of non-rapid eye movement (NREM) sleep and are believed to mediate many sleep-related functions, from memory consolidation to cortical development. Spindles differ in location, frequency, and association with slow waves, but whether this heterogeneity may reflect different physiological processes and potentially serve different functional roles remains unclear. Here we utilized a unique opportunity to record intracranial depth EEG and single-unit activity in multiple brain regions of neurosurgical patients to better characterize spindle activity in human sleep. We find that spindles occur across multiple neocortical regions, and less frequently also in the parahippocampal gyrus and hippocampus. Most spindles are spatially restricted to specific brain regions. In addition, spindle frequency is topographically organized with a sharp transition around the supplementary motor area between fast (13-15Hz) centroparietal spindles often occurring with slow wave up-states, and slow (9-12Hz) frontal spindles occurring 200ms later on average. Spindle variability across regions may reflect the underlying thalamocortical projections. We also find that during individual spindles, frequency decreases within and between regions. In addition, deeper sleep is associated with a reduction in spindle occurrence and spindle frequency. Frequency changes between regions, during individual spindles, and across sleep may reflect the same phenomenon, the underlying level of thalamocortical hyperpolarization. Finally, during spindles neuronal firing rates are not consistently modulated, although some neurons exhibit phase-locked discharges. Overall, anatomical considerations can account well for regional spindle characteristics, while variable hyperpolarization levels can explain differences in spindle frequency.
doi:10.1523/JNEUROSCI.2604-11.2011
PMCID: PMC3270580  PMID: 22159098
23.  Regional Slow Waves and Spindles in Human Sleep 
Neuron  2011;70(1):153-169.
SUMMARY
The most prominent EEG events in sleep are slow waves, reflecting a slow (<1 Hz) oscillation between up and down states in cortical neurons. It is unknown whether slow oscillations are synchronous across the majority or the minority of brain regions—are they a global or local phenomenon? To examine this, we recorded simultaneously scalp EEG, intracerebral EEG, and unit firing in multiple brain regions of neurosurgical patients. 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.
doi:10.1016/j.neuron.2011.02.043
PMCID: PMC3108825  PMID: 21482364
24.  3D surface maps link local atrophy & Fast Ripples in human epileptic hippocampus 
Annals of Neurology  2009;66(6):783-791.
Objective
There is compelling evidence that pathological high frequency oscillations (HFOs) called Fast Ripples (FR, 150–500 Hz) reflect abnormal synchronous neuronal discharges in areas responsible for seizure genesis in patients with mesial temporal lobe epilepsy (MTLE). It is hypothesized that morphological changes associated with hippocampal atrophy (HA) contribute to the generation of FR, yet there is limited evidence that hippocampal FR-generating sites correspond with local areas of atrophy.
Methods
Interictal HFOs were recorded from hippocampal microelectrodes in ten patients with MTLE. Rates of FR and Ripple discharge from each microelectrode were evaluated in relation to local measures of HA obtained using 3D MRI hippocampal modeling.
Results
Rates of FR discharge were three times higher in areas of significant local HA compared to rates in non-atrophic areas. Furthermore, FR occurrence correlated directly with the severity of damage in these local atrophic regions. In contrast, we found no difference in rates of Ripple discharge between local atrophic and non-atrophic areas.
Interpretation
The proximity between local HA and microelectrode-recorded FR suggest morphological changes such as neuron loss and synaptic reorganization may contribute to the generation of FR. Pathological HFOs, such as FR, may provide a reliable surrogate marker of abnormal neuronal excitability in hippocampal areas responsible for the generation of spontaneous seizures in patients with MTLE. Based on these data, it is possible that MRI-based measures of local HA could identify FR-generating regions, and thus provide a non-invasive means to localize epileptogenic regions in hippocampus.
doi:10.1002/ana.21703
PMCID: PMC3299311  PMID: 20035513
25.  Internally generated preactivation of single neurons in human medial frontal cortex predicts volition 
Neuron  2011;69(3):548-562.
Understanding how self-initiated behavior is encoded by neuronal circuits in the human brain remains elusive. We recorded the activity of 1019 neurons while twelve subjects performed self-initiated finger movement. We report progressive neuronal recruitment over ~1500 ms before subjects report making the decision to move. We observed progressive increase or decrease in neuronal firing rate, particularly in the supplementary motor area (SMA), as the reported time of decision was approached. A population of 256 SMA neurons is sufficient to predict in single trials the impending decision to move with accuracy greater than 80% already 700 ms prior to subjects’ awareness. Furthermore, we predict, with a precision of a few hundred ms, the actual time point of this voluntary decision to move. We implement a computational model whereby volition emerges once a change in internally generated firing rate of neuronal assemblies crosses a threshold.
doi:10.1016/j.neuron.2010.11.045
PMCID: PMC3052770  PMID: 21315264

Results 1-25 (41)