David E. Millett

Correlation Between BOLD fMRI and Theta-Band Local Field Potentials in the Human Hippocampal Area

The relation between the blood-oxygen-level-dependent (BOLD) signal, which forms the basis of functional magnetic resonance imaging (fMRI), and underlying neural activity is not well understood. We performed high-resolution fMRI in patients scheduled for implantation with depth electrodes for seizure monitoring while they navigated a virtual environment. We then recorded local field potentials (LFPs) and neural firing rate directly from the hippocampal area of the same subjects during the same task. Comparing BOLD signal changes with 396 LFP and 185 neuron recordings in the hippocampal area, we found that BOLD signal changes correlated positively with LFP power changes in the theta-band (4-8 Hz). This correlation, however, was largely present for parahippocampal BOLD signal changes; BOLD changes in the hippocampus correlated weakly or not at all with LFP power changes. We did not find a significant relationship between BOLD activity and neural firing rate in either region, which could not be accounted for by a lesser tendency for neurons to respond or a greater tendency for neurons to habituate to the task. Strengthening the idea of a dissociation between LFP power and neural firing rate in their relation to the BOLD signal, simultaneously recorded LFP power and neural firing rate changes were uncorrelated across electrodes. Together, our results suggest that the BOLD signal in the human hippocampal area has a more heterogenous relationship with underlying neural activity than has been described previously in other brain regions.

Extracting kinetic information from human motor cortical signals

Brain machine interfaces (BMIs) have the potential to provide intuitive control of neuroprostheses to restore grasp to patients with paralyzed or amputated upper limbs. For these neuroprostheses to function, the ability to accurately control grasp force is critical. Grasp force can be decoded from neuronal spikes in monkeys, and hand kinematics can be decoded using electrocorticogram (ECoG) signals recorded from the surface of the human motor cortex. We hypothesized that kinetic information about grasping could also be extracted from ECoG, and sought to decode continuously-graded grasp force. In this study, we decoded isometric pinch force with high accuracy from ECoG in 10 human subjects. The predicted signals explained from 22% to 88% (60 ± 6%, mean ± SE) of the variance in the actual force generated. We also decoded muscle activity in the finger flexors, with similar accuracy to force decoding. We found that high gamma band and time domain features of the ECoG signal were most informative about kinetics, similar to our previous findings with intracortical LFPs. In addition, we found that peak cortical representations of force applied by the index and little fingers were separated by only about 4mm. Thus, ECoG can be used to decode not only kinematics, but also kinetics of movement. This is an important step toward restoring intuitively-controlled grasp to impaired patients.

A co-registration approach for electrocorticogram electrode localization using post-implantation MRI and CT of the head

Electrocorticogram (ECoG) signals are acquired from electrodes that are surgically implanted into the subdural space of the brain. Although this procedure is usually performed for clinical purposes such as defining seizure locations and/or brain mapping, ECoG signals can also be used for characterizing the electrophysiology underlying various behaviors or for brain-computer interface applications. Therefore, defining the anatomical location of ECoG electrodes is an important process for contextual interpretation of the results. Current techniques utilize semi-automated statistical methods to co-register ECoG electrodes from either post-implantation X-rays or computer tomography (CT) images with a pre-implantation magnetic resonance imaging (MRI) of the brain. However, due to brain deformation caused by surgical electrode implantation, ECoG electrode locations must be projected onto the brain surface of the pre-implantation MRI, which may result in error. The authors present an exploratory study where post-implantation MRI images were successfully used for co-registration with post-implantation CT images of ECoG electrodes without the need for projection. By using postimplantation CT and MRI images which preserve the brain deformation, error in defining ECoG electrode locations may be reduced or eliminated.

An in vitro seizure model from human hippocampal slices using multi-electrode arrays.

Temporal lobe epilepsy is a neurological condition marked by seizures, typically accompanied by large amplitude synchronous electrophysiological discharges, affecting a variety of mental and physical functions. The neurobiological mechanisms responsible for the onset and termination of seizures are still unclear. While pharmacological therapies can suppress the symptoms of seizures, typically 30% of patients do not respond well to drug control. Unilateral temporal lobectomy, a procedure in which a substantial part of the hippocampal formation and surrounding tissue is removed, is a common surgical treatment for medically refractory epilepsy. In this study, we have developed an in vitro model of epilepsy using human hippocampal slices resected from patients suffering from intractable mesial temporal lobe epilepsy. We show that using a planar multi-electrode array system, spatio-temporal inter-ictal like activity can be consistently recorded in high-potassium (8 mM), low-magnesium (0.25 mM) artificial cerebral spinal fluid with 4-aminopyridine (100 μM) added. The induced epileptiform discharges can be recorded in different subregions of the hippocampus, including dentate, CA1 and subiculum. This new paradigm will allow the study of seizure generation in different subregions of hippocampus simultaneously, as well as propagation of seizure activity throughout the intrinsic circuitry of hippocampus. This experimental model also should provide insights into seizure control and prevention, while providing a platform to develop novel, anti-seizure therapeutics.

State and trajectory decoding of upper extremity movements from electrocorticogram

Electrocorticography has been widely explored as a long-term signal acquisition platform for brain-computer interface (BCI) control of upper extremity prostheses. However, a comprehensive study of elementary upper extremity movements and their relationship to electrocorticogram (ECoG) signals has yet to be performed. This study examines whether kinematic parameters of 6 elementary upper extremity movements can be decoded from ECoG signals in 3 subjects undergoing subdural electrode placement for epilepsy surgery evaluation. To this end, we propose a 2-stage decoding approach that consists of a state decoder to determine idle/move states, followed by a Kalman filter-based trajectory decoder. This proposed decoder successfully classified idle/move states with an average accuracy of 91%, and the correlation between decoded and measured trajectory averaged 0.70 for position and 0.68 for velocity. These performances represent an improvement over a simple regression-based approach.

Electrocorticogram encoding of upper extremity movement trajectories

Electrocorticogram (ECoG)-based brain computer interfaces (BCI) can potentially control upper extremity pros-theses to restore independent function to paralyzed individuals. However, current research is mostly restricted to the offline decoding of finger or 2D arm movement trajectories, and these results are modest. This study seeks to improve the fundamental understanding of the ECoG signal features underlying upper extremity movements to guide better BCI design. Subjects undergoing ECoG electrode implantation performed a series of elementary upper extremity movements in an intermittent flexion and extension manner. It was found that movement velocity, θ̇, had a high positive (negative) correlation with the instantaneous power of the ECoG high-γ band (80-160 Hz) during flexion (extension). Also, the correlation was low during idling epochs. Visual inspection of the ECoG high-γ band revealed power bursts during flexion/extension events that had a waveform that strongly resembled the corresponding flexion/extension event as seen on θ̇. These high-γ bursts were present in all elementary movements, and were spatially distributed in a somatotopic fashion. Thus, it can be concluded that the high-γ power of ECoG strongly encodes for movement trajectories, and can be used as an input feature in future BCIs.

Sensitivity and specificity of upper extremity movements decoded from electrocorticogram

Electrocorticogram (ECoG)-based brain computer interfaces (BCI) can potentially be used for control of arm prostheses. Restoring independent function to BCI users with such a system will likely require control of many degrees-of-freedom (DOF). However, our ability to decode many-DOF arm movements from ECoG signals has not been thoroughly tested. To this end, we conducted a comprehensive study of the ECoG signals underlying 6 elementary upper extremity movements. Two subjects undergoing ECoG electrode grid implantation for epilepsy surgery evaluation participated in the study. For each task, their data were analyzed to design a decoding model to classify ECoG as idling or movement. The decoding models were found to be highly sensitive in detecting movement, but not specific in distinguishing between different movement types. Since sensitivity and specificity must be traded-off, these results imply that conventional ECoG grids may not provide sufficient resolution for decoding many-DOF upper extremity movements.

Spatio-temporal inter-ictal activity recorded from human epileptic hippocampal slices

Epilepsy is a medical syndrome that produces seizures affecting a variety of mental and physical functions. The actual mechanisms of the onset and termination of the seizure are still unclear. While medical therapies can suppress the symptoms of seizures, 30% of patients do not respond well. Temporal lobectomy is a common surgical treatment for medically refractory epilepsy. Part of the hippocampus is removed from the patient. In this study, we have developed an in vitro epileptic model in human hippocampal slices resected from patients suffering from intractable mesial temporal lobe epilepsy. Using a planar multielectrode array system, spatio-temporal inter-ictal activity can be consistently recorded in high-potassium (8 mM), low-magnesium (0.25 mM) aCSF with additional 100 μM 4-aminopyridine. The induced inter-ictal activity can be recorded in different regions including dentate, CA1 and Subiculum. We hope the experimental model built in this study will help us understand more about seizure generation, as well as providing insights into prevention and novel therapeutics.

Dysregulation of PINCH signaling in mesial temporal epilepsy

Mounting evidence suggests that inflammation is important in epileptogenesis. Particularly Interesting New Cysteine Histidine-rich (PINCH) protein is a highly conserved, LIM-domain protein known to interact with hyperphosphorylated Tau. We assessed PINCH expression in resected epileptogenic human hippocampi and further explored the relationships among PINCH, hpTau and associated kinases. Resected hippocampal tissue from 7 patients with mesial temporal lobe epilepsy (MTLE) was assessed by Western analyses to measure levels of PINCH and hyperphosphorylated Tau, as well as changes in phosphorylation levels of associated kinases AKT and GSK3β in comparison to normal control tissue. Immunolabeling was also conducted to evaluate PINCH and hpTau patterns of expression, co-localization and cell-type specific expression. Hippocampal PINCH was increased by 2.6 fold in the epilepsy cases over controls and hpTau was increased 10 fold over control. Decreased phospho-AKT and phospho-GSK3β in epilepsy tissue suggested involvement of this pathway in MTLE. PINCH and hpTau co-localized in some neurons in MTLE tissue. While PINCH was expressed by both neurons and astrocytes in MTLE tissue, hpTau was extracellular or associated with neurons. PINCH was absent from the serum of control subjects but readily detectable from the serum of patients with chronic epilepsy. Our study describes the expression of PINCH and points to AKT/GSK3β signaling dysregulation as a possible pathway in hpTau formation in MTLE. In view of the interactions between hpTau and PINCH, understanding the role of PINCH in MTLE may provide increased understanding of mechanisms leading to inflammation and MTLE epileptogenesis and a potential biomarker for drug-resistant epilepsy.

Unstable periodic orbits in human epileptic hippocampal slices.

Inter-ictal activity is studied in hippocampal slices resected from patients with epilepsy using local field potential recording. Inter-ictal activity in the dentate gyrus (DG) is induced by high-potassium (8 mM), low-magnesium (0.25 mM) aCSF with additional 100 μM 4-aminopyridine(4-AP). The dynamics of the inter-ictal activity is investigated by developing the first return map with inter-pulse intervals. Unstable periodic orbits (UPOs) are detected in the hippocampal slice at the DG area according to both the topological recurrence method and the periodic orbit transform method. Surrogate analysis suggests the presence of UPOs in hippocampal slices from patients with epilepsy. This finding also suggests that inter-ictal activity is a chaotic system and will allow us to apply chaos control techniques to manipulate inter-ictal activity.