Matthew S. D. Kerr

Reinstatement of distributed cortical oscillations occurs with precise spatiotemporal dynamics during successful memory retrieval

Significance Our results represent significant contributions to understanding the neural mechanisms and spatiotemporal dynamics governing neural reinstatement in two important ways. First, by using a cued recall memory task, our paradigm offers experimental control over retrieval. We compare reinstatement during correct and incorrect retrieval, and provide evidence that retrieval recovers a gradually changing representation of temporal context. These data provide support for mental time travel hypothesized to underlie episodic memory. Second, leveraging the high temporal precision afforded by intracranial recordings, we investigate the precise timing of reinstatement and demonstrate that retrieval may reactivate cortical representations of a memory on a faster timescale than during encoding. Our data complement previous studies demonstrating faster replay of patterns associated with a prior episode. Reinstatement of neural activity is hypothesized to underlie our ability to mentally travel back in time to recover the context of a previous experience. We used intracranial recordings to directly examine the precise spatiotemporal extent of neural reinstatement as 32 participants with electrodes placed for seizure monitoring performed a paired-associates episodic verbal memory task. By cueing recall, we were able to compare reinstatement during correct and incorrect trials, and found that successful retrieval occurs with reinstatement of a gradually changing neural signal present during encoding. We examined reinstatement in individual frequency bands and individual electrodes and found that neural reinstatement was largely mediated by temporal lobe theta and high-gamma frequencies. Leveraging the high temporal precision afforded by intracranial recordings, our data demonstrate that high-gamma activity associated with reinstatement preceded theta activity during encoding, but during retrieval this difference in timing between frequency bands was absent. Our results build upon previous studies to provide direct evidence that successful retrieval involves the reinstatement of a temporal context, and that such reinstatement occurs with precise spatiotemporal dynamics.

Formation of a cytoplasmic salt bridge network in the matrix state is a fundamental step in the transport mechanism of the mitochondrial ADP/ATP carrier.

Mitochondrial ADP/ATP carriers catalyze the equimolar exchange of ADP and ATP across the mitochondrial inner membrane. Structurally, they consist of three homologous domains with a single substrate binding site. They alternate between a cytoplasmic and matrix state in which the binding site is accessible to these compartments for binding of ADP or ATP. It has been proposed that cycling between states occurs by disruption and formation of a matrix and cytoplasmic salt bridge network in an alternating way, but formation of the latter has not been shown experimentally. Here, we show that state-dependent formation of the cytoplasmic salt bridge network can be demonstrated by measuring the effect of mutations on the thermal stability of detergent-solubilized carriers locked in a specific state. For this purpose, mutations were made to increase or decrease the overall interaction energy of the cytoplasmic network. When locked in the cytoplasmic state by the inhibitor carboxyatractyloside, the thermostabilities of the mutant and wild-type carriers were similar, but when locked in the matrix state by the inhibitor bongkrekic acid, they correlated with the predicted interaction energy of the cytoplasmic network, demonstrating its formation. Changing the interaction energy of the cytoplasmic network also had a profound effect on the kinetics of transport, indicating that formation of the network is a key step in the transport cycle. These results are consistent with a unique alternating access mechanism that involves the simultaneous rotation of the three domains around a central translocation pathway.

Performing behavioral tasks in subjects with intracranial electrodes.

Patients having stereo-electroencephalography (SEEG) electrode, subdural grid or depth electrode implants have a multitude of electrodes implanted in different areas of their brain for the localization of their seizure focus and eloquent areas. After implantation, the patient must remain in the hospital until the pathological area of brain is found and possibly resected. During this time, these patients offer a unique opportunity to the research community because any number of behavioral paradigms can be performed to uncover the neural correlates that guide behavior. Here we present a method for recording brain activity from intracranial implants as subjects perform a behavioral task designed to assess decision-making and reward encoding. All electrophysiological data from the intracranial electrodes are recorded during the behavioral task, allowing for the examination of the many brain areas involved in a single function at time scales relevant to behavior. Moreover, and unlike animal studies, human patients can learn a wide variety of behavioral tasks quickly, allowing for the ability to perform more than one task in the same subject or for performing controls. Despite the many advantages of this technique for understanding human brain function, there are also methodological limitations that we discuss, including environmental factors, analgesic effects, time constraints and recordings from diseased tissue. This method may be easily implemented by any institution that performs intracranial assessments; providing the opportunity to directly examine human brain function during behavior.

Cortical control of reach and grasp kinematics in a virtual environment using musculoskeletal modeling software

Recently there has been a major initiative to develop a Brain-Machine Interface (BMI) for dexterous control of an upper-limb neuroprosthesis. This paper describes the use of a virtual environment using Musculoskeletal Modeling Software as a model system to test and evaluate cortical algorithms for predicting reach and grasp kinematics. Simultaneous neural and motion tracking data was acquired from a non-human primate trained to perform a center-out reach-and-grasp task. A Kalman Filter was designed to simultaneously predict kinematics of the arm, hand, and fingers with high accuracy (avg r=0.83; avg RMSE=13.7%). In lieu of an advanced mechanical limb, the decoded output was used to manipulate a fully articulated 18-DoF arm in a virtual environment using MSMS. This platform lays the foundation for future closed-loop experiments with non-human primates to demonstrate a BMI for dexterous control of the hand and fingers.

Multivariate analysis of SEEG signals during seizure

Epilepsy is a neurological disorder that affects tens of millions of people every year and is characterized by sudden-onset seizures which are often associated with physical convulsions. Effective treatment and management of epilepsy would be greatly improved if convulsions could be caught quickly through early seizure detection. However, this is still a largely open problem due to the challenge of finding a robust statistic from the neural measurements. This paper suggests a new multivariate statistic by combining spectral techniques with matrix theory. Specifically, stereoelectroencephalography (SEEG) data was used to generate a series of coherence connectivity matrices which were then examined using singular value decomposition. Tracking the relative angles of the first singular vectors generated from this data provides an effective way of defining the most dominant characteristics of the SEEG during the normal, the pre-ictal, and the ictal states. This paper indicates that the first singular vector has a characteristic direction indicative of the seizure state and illustrates a data analysis method that incorporates all neural data as opposed to a small selection of channels.

Lucky Rhythms in Orbitofrontal Cortex Bias Gambling Decisions in Humans

It is well established that emotions influence our decisions, yet the neural basis of this biasing effect is not well understood. Here we directly recorded local field potentials from the OrbitoFrontal Cortex (OFC) in five human subjects performing a financial decision-making task. We observed a striking increase in gamma-band (36–50 Hz) oscillatory activity that reflected subjects’ decisions to make riskier choices. Additionally, these gamma rhythms were linked back to mismatched expectations or “luck” occurring in past trials. Specifically, when a subject expected to win but lost, the trial was defined as “unlucky” and when the subject expected to lose but won, the trial was defined as “lucky”. Finally, a fading memory model of luck correlated to an objective measure of emotion, heart rate variability. Our findings suggest OFC may play a pivotal role in processing a subject’s internal (emotional) state during financial decision-making, a particularly interesting result in light of the more recent “cognitive map” theory of OFC function.

The Role of Associative Cortices and Hippocampus during Movement Perturbations

Although motor control has been extensively studied, most research involving neural recordings has focused on primary motor cortex, pre-motor cortex, supplementary motor area, and cerebellum. These regions are involved during normal movements, however, associative cortices and hippocampus are also likely involved during perturbed movements as one must detect the unexpected disturbance, inhibit the previous motor plan, and create a new plan to compensate. Minimal data is available on these brain regions during such “robust” movements. Here, epileptic patients implanted with intracerebral electrodes performed reaching movements while experiencing occasional unexpected force perturbations allowing study of the fronto-parietal, limbic and hippocampal network at unprecedented high spatial, and temporal scales. Areas including orbitofrontal cortex (OFC) and hippocampus showed increased activation during perturbed trials. These results, coupled with a visual novelty control task, suggest the hippocampal MTL-P300 novelty response is modality independent, and that the OFC is involved in modifying motor plans during robust movement.

The precuneus may encode irrationality in human gambling

Humans often make irrational decisions, especially psychiatric patients who have dysfunctional cognitive and emotional circuitry. Understanding the neural basis of decision-making is therefore essential towards patient management, yet current studies suffer from several limitations. Functional magnetic resonance imaging (fMRI) studies in humans have dominated decision-making neuroscience, but have poor temporal resolution and the blood oxygenation level-dependent signal is only a proxy for neural activity. On the other hand, lesion studies in humans used to infer functionality in decision-making lack characterization of neural activity altogether. Using a combination of local field potential recordings in human subjects performing a financial decision-making task, spectral analyses, and non-parametric cluster statistics, we analyzed the activity in the precuneus. In nine subjects, the neural activity modulated significantly between rational and irrational trials in the precuneus (p <; 0.001). In particular, high-frequency activity (70-100 Hz) increased when irrational decisions were made. Although preliminary, these results suggest suppression of gamma rhythms via electrical stimulation in the precuneus as a therapeutic intervention for pathological decision-making.

Winning versus losing during gambling and its neural correlates

Humans often make decisions which maximize an internal utility function. For example, humans often maximize their expected reward when gambling and this is considered as a “rational” decision. However, humans tend to change their betting strategies depending on how they “feel”. If someone has experienced a losing streak, they may “feel” that they are more likely to win on the next hand even though the odds of the game have not changed. That is, their decisions are driven by their emotional state. In this paper, we investigate how the human brain responds to wins and losses during gambling. Using a combination of local field potential recordings in human subjects performing a financial decision-making task, spectral analyses, and non-parametric cluster statistics, we investigated whether neural responses in different cognitive and limbic brain areas differ between wins and losses after decisions are made. In eleven subjects, the neural activity modulated significantly between win and loss trials in one brain region: the anterior insula (p = 0.01). In particular, gamma activity (30-70 Hz) increased in the anterior insula when subjects just realized that they won. Modulation of metabolic activity in the anterior insula has been observed previously in functional magnetic resonance imaging studies during decision making and when emotions are elicited. However, our study is able to characterize temporal dynamics of electrical activity in this brain region at the millisecond resolution while decisions are made and after outcomes are revealed.

High frequency activity correlates of robust movement in humans

The neural circuitry underlying fast robust human motor control is not well understood. In this study we record neural activity from multiple stereotactic encephalograph (SEEG) depth electrodes in a human subject while he/she performs a center-out reaching task holding a robotic manipulandum that occasionally introduces an interfering force field. Collecting neural data from humans during motor tasks is rare, and SEEG provides an unusual opportunity to examine neural correlates of movement at a millisecond time scale in multiple brain regions. Time-frequency analysis shows that high frequency activity (50-150 Hz) increases significantly in the left precuneus and left hippocampus when the subject is compensating for a perturbation to their movement. These increases in activity occur with different durations indicating differing roles in the motor control process.