Faculty Bibliography

Verbal working memory (vWM) involves storing and manipulating information in phonological sensory input. An influential theory of vWM proposes that manipulation is carried out by a central executive while storage is performed by two interacting systems: a phonological input buffer that captures sound-based information and an articulatory rehearsal system that controls speech motor output. Whether, when and how neural activity in the brain encodes these components remains unknown. Here we read out the contents of vWM from neural activity in human subjects as they manipulated stored speech sounds. As predicted, we identified storage systems that contained both phonological sensory and articulatory motor representations. Unexpectedly, however, we found that manipulation did not involve a single central executive but rather involved two systems with distinct contributions to successful manipulation. We propose, therefore, that multiple subsystems comprise the central executive needed to manipulate stored phonological input for articulatory motor output in vWM.

The two most common types of temporal lobe epilepsy are medial temporal sclerosis epilepsy (TLE-MTS) and MRI-normal temporal lobe epilepsy (TLE-no). TLE-MTS is specified by its stereotyped focus and spread pattern of neuronal damage, with pronounced neuronal loss in the hippocampus. TLE-no exhibits normal-appearing hippocampus and more widepsread neuronal loss. In both cases neuronal loss spread appears to be constrained by the white matter connections. Both varieties of epilepsy reveal pathological abnormalities in increased mean diffusivity (MD). We model MD distribution as a simple consequence of the propagation of neuronal damage. By applying this model on the structural brain connectivity network of healthy subjects we can predict at group level the mean diffusivity gray matter change in the epilepsy cohorts relative to a control group. DTI images were acquired from 10 patients with TLE-MTS, 11 patients with TLE-no, and 35 healthy subjects. Statistical validation at the group level suggests high correlation with measured neuronal loss (R = 0.56 for the TLE-MTS group and R = 0.364 for the TLE-no group). The results of this exploratory work pave the way for potential future clinical application of the proposed model on individual patients, including predicting neuronal loss spread, identification of seizure onset zones, and helping in surgical planning.

Surface-based cortical thickness (CT) analyses are increasingly being used to investigate variations in brain morphology across the spectrum of brain health, from neurotypical to neuropathological. An outstanding question is whether individual differences in cortical morphology, such as regionally increased or decreased CT, are associated with domain-specific performance deficits in healthy adults. Since CT studies are correlational, they cannot establish causality between brain morphology and cognitive performance. A direct comparison with classic lesion methods is needed to determine whether the regional specificity of CT-cognition correlations is similar to that observed in patients with brain lesions. We address this question by comparing the neuroanatomical overlap of effects when 1) whole brain vertex-wise CT is tested as a correlate of performance variability on a commonly used neuropsychological test of executive function, Trailmaking Test Part B (TMT-B), in healthy adults and 2) voxel-based lesion-symptom mapping (VBLSM) is used to map lesion location to performance decrements on the same task in patients with frontal lobe lesions. We found that reduced performance on the TMT-B was associated with increased CT in bilateral prefrontal regions in healthy adults and that results spatially overlapped in the left dorsomedial prefrontal cortex with findings from the VBLSM analysis in patients with frontal brain lesions. Findings indicate that variations in the structural integrity of the left dorsomedial prefrontal lobe, ranging from individual CT differences in healthy adults to structural lesions in patients with neurological disorders, are associated with poor performance on the TMT-B. These converging results suggest that the left dorsomedial prefrontal region houses a critical region for the complex processing demands of TMT-B, which include visuomotor tracking, sequencing, and cognitive flexibility.

OBJECTIVE: We assessed whether presurgical resting state functional magnetic resonance imaging (fMRI) provides information for distinguishing temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) from TLE without MTS (TLE-noMTS). METHODS: Thirty-four patients with TLE and 34 sex-/age-matched controls consented to a research imaging protocol. MTS status was confirmed by histologic evaluation of surgical tissue (TLE-MTS = 16; TLE-noMTS = 18). The fractional amplitude of low-frequency fluctuations (fALFFs) in the blood oxygen level-dependent (BOLD) resting-state fMRI signal, a marker of local metabolic demand at rest, was averaged at five regions of interest (ROIs; hippocampus, amygdala, frontal, occipital, and temporal lobe), along with corresponding volume and cortical thickness estimates. ROIs were labeled ipsilateral or contralateral according to seizure lateralization and compared across TLE-MTS, TLE-noMTS, and healthy controls (HCs). MTS status was regressed on ipsilateral hippocampal volume and fALFF to test for independent contributions. RESULTS: The TLE-MTS group had reduced fALFF in the ipsilateral amygdala and hippocampus; whereas, the TLE-noMTS group had marginally reduced fALFF in the ipsilateral amygdala but not hippocampus. These results were consistently obtained with and without application of global signal regression (GSR). Ipsilateral hippocampal volume contributed to 37% of the variance in MTS status (p < 0.001) and fALFF contributed an additional 10% (p = 0.021). Two MTS cases were accurately classified with fALFF but not volume, and three were accurately classified with volume but not fALFF. At the lobar level, fALFF (with GSR) was reduced in the ipsilateral temporal and bilateral frontal lobes of patients with TLE-MTS and bilateral frontal lobes of patients with TLE-noMTS in the context of normal cortical thickness. SIGNIFICANCE: This study indicates that resting-state fMRI provides complementary functional information for MTS classification. Findings validate fALFF as a measure of regional brain integrity in TLE and highlight the value of using multi-modal imaging to provide independent diagnostic information in presurgical epilepsy evaluations.

In animal models, inflammation is both a cause and consequence of seizures. Less is known about the role of inflammation in human epilepsy. We performed positron emission tomography (PET) using a radiotracer sensitive to brain inflammation in a patient with frontal epilepsy ~36 h after a seizure as well as during a seizure-free period. When statistically compared to a group of 12 matched controls, both of the patient's scans identified a frontal (supplementary motor area) region of increased inflammation corresponding to his clinically defined seizure focus, but the postseizure scan showed significantly greater inflammation intensity and spatial extent. These results provide new information about transient and chronic neuroinflammation in human epilepsy and may be relevant to understanding the process of epileptogenesis and guiding therapy.

We present a new approach to extracting low-dimensional neural trajectories that summarize the electrocorticographic (ECoG) signals recorded with high-channel-count electrode arrays implanted subdurally. In our approach, Hidden-Markov Factor Analysis (HMFA), a finite set of factor analyzers are used to model the relationship between the high-dimensional ECoG neural space and a low-dimensional latent neural space; the factor analyzers at different time points are in turn linked together with a hidden Markov model. The recorded ECoG signals were band-pass filtered such that our analysis was focused on a sub-band (76-100Hz) of high gamma. HMFA affords the quantization of the ECoG neural space and dimensionality reduction in a common probabilistic space. We applied this method to the ECoG recordings of 2 subjects who responded with button presses to audiovisual stimuli in an experimental task. Using a goodness-of-fit metric that measures how well the ECoG activity of each electrode can be predicted by all the other electrodes, we found that HMFA performed best when compared with Gaussian-Process Factor Analysis (GPFA) and other related spatiotemporal modeling techniques. In contradistinction to HMFA, GPFA and the other techniques integrate temporal smoothing with dimensionality reduction. We believe that this method will provide a powerful tool for relating high-channel-count ECoG signals to the perception and behavior of subjects.

To augment neural monitoring, a minimally intrusive multi-modal capture system was designed and implemented in the epilepsy clinic. This system provides RGB-D audio-video synchronized with patient electrocorticography (ECoG), which records neural activity across cortex. We propose an automated approach to studying the human brain in a naturalistic setting. We demonstrate coarse functional mapping of ECoG electrodes correlated to contralateral arm movements. Motor electrode mapping was generated by analyzing continuous movement data recorded over several hours from epilepsy patients in hospital rooms. From these recordings we estimate the kinematics of patient hand movement behaviors using computer vision algorithms. We compare movement behaviors to neural data collected from ECoG, specifically high-γ (70-110 Hz) spectral features. We present a functional map of electrode responses to natural arm movements, generated using a statistical test. We demonstrate that our approach has the potential to aid in the development of automated functional brain mapping using continuous video and neural recordings of patients in clinical settings.

Interactions between the hippocampus and the cortex are critical for memory. Interictal epileptiform discharges (IEDs) identify epileptic brain regions and can impair memory, but the mechanisms by which they interact with physiological patterns of network activity are mostly undefined. We show in a rat model of temporal lobe epilepsy that spontaneous hippocampal IEDs correlate with impaired memory consolidation, and that they are precisely coordinated with spindle oscillations in the prefrontal cortex during nonrapid-eye-movement (NREM) sleep. This coordination surpasses the normal physiological ripple-spindle coupling and is accompanied by decreased ripple occurrence. IEDs also induce spindles during rapid-eye movement (REM) sleep and wakefulness-behavioral states that do not naturally express these oscillations-by generating a cortical 'down' state. In a pilot clinical examination of four subjects with focal epilepsy, we confirm a similar correlation of temporofrontal IEDs with spindles over anatomically restricted cortical regions. These findings imply that IEDs may impair memory via the misappropriation of physiological mechanisms for hippocampal-cortical coupling, which suggests a target for the treatment of memory impairment in epilepsy.

INTRODUCTION: Depression and memory dysfunction significantly impact the quality of life of patients with epilepsy. Current therapies for these cognitive and psychiatric comorbidities are limited. We explored the efficacy and safety of transcranial direct current stimulation (TDCS) for treating depression and memory dysfunction in patients with temporal lobe epilepsy (TLE). METHODS: Thirty-seven (37) adults with well-controlled TLE were enrolled in a double-blinded, sham-controlled, randomized, parallel-group study of 5days of fixed-dose (2mA, 20min) TDCS. Subjects were randomized to receive either real or sham TDCS, both delivered over the left dorsolateral prefrontal cortex. Patients received neuropsychological testing and a 20-minute scalp EEG at baseline immediately after the TDCS course and at 2- and 4-week follow-up. RESULTS: There was improvement in depression scores immediately after real TDCS, but not sham TDCS, as measured by changes in the Beck Depression Inventory (BDI change: -1.68 vs. 1.27, p<0.05) and NDDI-E (-0.83 vs. 0.9091, p=0.05). There was no difference between the groups at the 2- or 4-week follow-up. There was no effect on delayed or working memory performance. Transcranial direct current stimulation was well-tolerated and did not increase seizure frequency or interictal discharge frequency. Transcranial direct current stimulation induced an increase in delta frequency band power over the frontal region and delta, alpha, and theta band power in the occipital region after real stimulation compared to sham stimulation, although the difference did not reach statistical significance. DISCUSSION: This study provides evidence for the use of TDCS as a safe and well-tolerated nonpharmacologic approach to improving depressive symptoms in patients with well-controlled TLE. However, there were no changes in memory function immediately following or persisting after a stimulation course. Further studies may determine optimal stimulation parameters for maximal mood benefit.