Altered brain functional connectivity induced by physical exercise may improve neuropsychological functions in patients with benign epilepsy.

OBJECTIVE: The objective of this study was to elucidate alteration in functional connectivity (FC) in patients with benign epilepsy with centrotemporal spikes (BECTS) as induced by physical exercise therapy and their correlation to the neuropsychological (NP) functions. METHODS: We analyzed 115 artifact- and spike-free 2-second epochs extracted from resting state EEG recordings before and after 5weeks of physical exercise in eight patients with BECTS. The exact Low Resolution Electromagnetic Tomography (eLORETA) was used for source reconstruction. We evaluated the cortical current source density (CSD) power across five different frequency bands (delta, theta, alpha, beta, and gamma). Altered FC between 34 regions of interests (ROIs) was then examined using lagged phase synchronization (LPS) method. We further investigated the correlation between the altered FC measures and the changes in NP test scores. RESULTS: We observed changes in CSD power following the exercise for all frequency bands and statistically significant increases in the right temporal region for the alpha band. There were a number of altered FC between the cortical ROIs in all frequency bands of interest. Furthermore, significant correlations were observed between FC measures and NP test scores at theta and alpha bands. CONCLUSION: The increased localization power at alpha band may be an indication of the positive impact of exercise in patients with BECTS. Frequency band-specific alterations in FC among cortical regions were associated with the modulation of cognitive and NP functions. The significant correlation between FC and NP tests suggests that physical exercise may mitigate the severity of BECTS, thereby enhancing NP function.

Prospective Optimization with Limited Resources.

The future is uncertain because some forthcoming events are unpredictable and also because our ability to foresee the myriad consequences of our own actions is limited. Here we studied how humans select actions under such extrinsic and intrinsic uncertainty, in view of an exponentially expanding number of prospects on a branching multivalued visual stimulus. A triangular grid of disks of different sizes scrolled down a touchscreen at a variable speed. The larger disks represented larger rewards. The task was to maximize the cumulative reward by touching one disk at a time in a rapid sequence, forming an upward path across the grid, while every step along the path constrained the part of the grid accessible in the future. This task captured some of the complexity of natural behavior in the risky and dynamic world, where ongoing decisions alter the landscape of future rewards. By comparing human behavior with behavior of ideal actors, we identified the strategies used by humans in terms of how far into the future they looked (their "depth of computation") and how often they attempted to incorporate new information about the future rewards (their "recalculation period"). We found that, for a given task difficulty, humans traded off their depth of computation for the recalculation period. The form of this tradeoff was consistent with a complete, brute-force exploration of all possible paths up to a resource-limited finite depth. A step-by-step analysis of the human behavior revealed that participants took into account very fine distinctions between the future rewards and that they abstained from some simple heuristics in assessment of the alternative paths, such as seeking only the largest disks or avoiding the smaller disks. The participants preferred to reduce their depth of computation or increase the recalculation period rather than sacrifice the precision of computation.

Dopamine function and the efficiency of human movement.

To sustain successful behavior in dynamic environments, active organisms must be able to learn from the consequences of their actions and predict action outcomes. One of the most important discoveries in systems neuroscience over the last 15 years has been about the key role of the neurotransmitter dopamine in mediating such active behavior. Dopamine cell firing was found to encode differences between the expected and obtained outcomes of actions. Although activity of dopamine cells does not specify movements themselves, a recent study in humans has suggested that tonic levels of dopamine in the dorsal striatum may in part enable normal movement by encoding sensitivity to the energy cost of a movement, providing an implicit "motor motivational" signal for movement. We investigated the motivational hypothesis of dopamine by studying motor performance of patients with Parkinson disease who have marked dopamine depletion in the dorsal striatum and compared their performance with that of elderly healthy adults. All participants performed rapid sequential movements to visual targets associated with different risk and different energy costs, countered or assisted by gravity. In conditions of low energy cost, patients performed surprisingly well, similar to prescriptions of an ideal planner and healthy participants. As energy costs increased, however, performance of patients with Parkinson disease dropped markedly below the prescriptions for action by an ideal planner and below performance of healthy elderly participants. The results indicate that the ability for efficient planning depends on the energy cost of action and that the effect of energy cost on action is mediated by dopamine.

Scaling and coordination deficits during dynamic object manipulation in Parkinson's disease.

The ability to reach for and dynamically manipulate objects in a dexterous fashion requires scaling and coordination of arm, hand, and fingertip forces during reach and grasp components of this behavior. The neural substrates underlying dynamic object manipulation are not well understood. Insight into the role of basal ganglia-thalamocortical circuits in object manipulation can come from the study of patients with Parkinson's disease (PD). We hypothesized that scaling and coordination aspects of motor control are differentially affected by this disorder. We asked 20 PD patients and 23 age-matched control subjects to reach for, grasp, and lift virtual objects along prescribed paths. The movements were subdivided into two types, intensive (scaling) and coordinative, by detecting their underlying self-similarity. PD patients off medication were significantly impaired relative to control subjects for both aspects of movement. Intensive deficits, reduced peak speed and aperture, were seen during the reach. Coordinative deficits were observed during the reach, namely, the relative position along the trajectory at which peak speed and aperture were achieved, and during the lift, when objects tilted with respect to the gravitational axis. These results suggest that basal ganglia-thalamocortical circuits may play an important role in fine motor coordination. Dopaminergic therapy significantly improved intensive but not coordinative aspects of movements. These findings are consistent with a framework in which tonic levels of dopamine in the dorsal striatum encode the energetic cost of a movement, thereby improving intensive or scaling aspects of movement. However, repletion of brain dopamine levels does not restore finely coordinated movement.

Unconstrained reaching modulates eye-hand coupling.

Eye­hand coordination is a crucial element of goal-directed movements. However, few studies have looked at the extent to which unconstrained movements of the eyes and hand made to targets influence each other. We studied human participants who moved either their eyes or both their eyes and hand to one of three static or flashed targets presented in 3D space. The eyes were directed, and hand was located at a common start position on either the right or left side of the body. We found that the velocity and scatter of memory-guided saccades (flashed targets) differed significantly when produced in combination with a reaching movement than when produced alone. Specifically, when accompanied by a reach, peak saccadic velocities were lower than when the eye moved alone. Peak saccade velocities, as well as latencies, were also highly correlated with those for reaching movements, especially for the briefly flashed targets compared to the continuous visible target. The scatter of saccade endpoints was greater when the saccades were produced with the reaching movement than when produced without, and the size of the scatter for both saccades and reaches was weakly correlated. These findings suggest that the saccades and reaches made to 3D targets are weakly to moderately coupled both temporally and spatially and that this is partly the result of the arm movement influencing the eye movement. Taken together, this study provides further evidence that the oculomotor and arm motor systems interact above and beyond any common target representations shared by the two motor systems.

Alteration in brain connectivity in patients with Dravet syndrome after vagus nerve stimulation (VNS): exploration of its effectiveness using graph theory analysis with electroencephalography.

OBJECTIVE: Vagus nerve stimulation (VNS) is a nonpharmacologic therapeutic option for patients who have pharmaco-resistant Dravet syndrome (DS). Plentiful efforts have been made for delivering VNS to DS patients, but its effectiveness still requires further verification. We investigated the effectiveness of the VNS treatment of DS patients using brain connectivity analysis with electroencephalography (EEG). APPROACH: Twenty pharmaco-resistant DS patients were selected to undergo VNS implantation and classified into responder and non-responder groups after 24 months post-VNS. The effect of VNS between 6 months pre- and 6, 12, and 24 months post-VNS in all patients, responders, and non-responders on four different frequency categories of four brain parameters were compared using resting-state EEG. MAIN RESULTS: In alpha and beta bands, all patients showed positive results for characteristic path length (CPL), global efficiency (GE), and transitivity after VNS treatment, and changes in betweenness centrality (BC) were not significant. The difference in transitivity between responders and non-responders is more pronounced than those in CPL and GE are, in both the alpha (p < 0.015) and beta (p < 0.001) bands. There was an obvious change in BC, especially in the alpha band, as the hubs tended to move from frontal lobe to parietal lobe for responders; however, there was no change for the non-responders. SIGNIFICANCE: We investigated the alteration in brain connectivity of DS patients in alpha and beta bands during a long-term follow-up and found the responders have a decreased transitivity after the VNS treatment. Moreover, the hubs with high values in the alpha band tended to move from frontal lobe to parietal lobe for responders after VNS treatment.

Resolving kinematic redundancy in target-reaching movements with and without external constraint.

In the context of target-reaching movements that involve the arms, trunk and legs, we have delineated rules for apportioning motions amongst body segments, which would be valid for a range of target locations that require forward bending. We further attempted to determine whether the rules are altered when motion is restricted at the knee, obliging a re-apportioning of segment motions. For each participant moving with unrestricted joints to nine target locations, principal component analysis of the changes in orientation (i.e., excursions) of six chosen segments revealed that their coupling can be described by two effective degrees of freedom (DoFs), whose weighted combinations account for the segmental excursions. Investigating the similarities and differences among individuals, we found that a set of two effective DoFs could account for the segment excursions among the group of participants who flex their knees significantly, and another set of two for the group who do not. Comparing the motions with and without the knee joints braced, we found that for each individual participant a set of two (or in some cases three) effective DoFs derived from the unrestricted segment excursions could account well for the altered segment excursions when the participant reached for the targets with the knees restricted. Our findings imply that the redundancy of kinematic DoFs can be resolved by reliance on a small number of couplings of segmental excursions, and, in light of the robustness of these couplings against mechanical restriction of joint motion, suggest a neural rather than mechanical origin for them.

Changes in functional brain network topology after successful and unsuccessful corpus callosotomy for Lennox-Gastaut Syndrome.

Corpus callosotomy (CC) is an effective palliative surgical treatment for patients with Lennox-Gastaut Syndrome (LGS). However, research on the long-term functional effects of CC is sparse. We aimed to investigate these effects and their associated clinical conditions over the two years after CC. Long-term clinical EEG recordings of 30 patients with LGS who had good and bad seizure outcome after CC were collected and retrospectively studied. It was found that CC caused brain network 'hubs' to shift from paramedian to lateral regions in the good-recovery group, which reorganized the brain network into a more homogeneous state. We also found increased local clustering coefficients in patients with bad outcomes and decreases, implying enhanced network integration, in patients with good outcomes. The small worldness of brain networks in patients with good outcomes increased in the two years after CC, whereas it decreased in patients with bad outcomes. The covariation of small-worldness with the rate of reduction in seizure frequency suggests that this can be used as an indicator of CC outcome. Local and global network changes during the long-term state might be associated with the postoperative recovery process and could serve as indicators for CC outcome and long-term LGS recovery.

Electroencephalography Network Effects of Corpus Callosotomy in Patients with Lennox-Gastaut Syndrome.

OBJECTIVES: This study aimed to investigate the functional network effects of corpus callosotomy (CC), a well-recognized palliative surgical therapy for patients with Lennox-Gastaut syndrome (LGS). Specifically, we sought to gain insight into the effects of CC on LGS remission, based on brain networks in LGS by calculating network metrics and evaluating by network measures before and after surgery. METHODS: Electroencephalographic recordings made during preoperative and 3-month postoperative states in 14 patients with LGS who had undergone successful CC were retrospectively analyzed. First, undirected correlation matrices were constituted for the mathematical expression of functional networks. Then, we plotted these networks to analyze the effects of CC on connectivity. In addition, conventional local and global network measures were applied to evaluate differences in network topology between preoperative and postoperative states. RESULTS: In the preoperative state, hubs were mainly distributed around the paramedian regions. After CC, the hubs moved from the paramedian regions to the dual-hemisphere and even the lateral regions. Thus, the general connectivity state became more homogeneous, which was verified by network plots and statistical analysis of local measures. The results of global network measures indicated a decreased clustering coefficient in the delta band, decreased characteristic path length in both the delta and gamma bands, and increased global efficiency in the gamma band. CONCLUSION: Our results showed a consistent variation in the global brain network that converted to a small-world topology with an optimal balance of functional integration and segregation of the network. Such changes were positively correlated with satisfactory surgery results, which could be interpreted as being indicative of LGS recovery process after CC. For patients with refractory LGS along with no focal epileptogenic zone findings, which were not suitable for the resective surgical therapy, our results verified that CC could work as an effective surgical treatment option.

Spectral characteristics of intracranial electroencephalographic activity in patients with Lennox-Gastaut syndrome.

OBJECTIVE: The purpose of the current study was to characterize the frequency profiles of epileptogenic regions, independent of visible epileptiform discharges, in intracranial EEG (iEEG) recordings of Lennox-Gastaut syndrome (LGS) patients. METHODS: We selected eight LGS patients who underwent resective surgery in the absence of definite neuroimaging findings. We calculated the absolute and relative band powers of continuous spike-free iEEG data and compared the characteristics of the resected and remaining regions. RESULTS: For absolute band powers, there was a trend for higher absolute gamma band power in the remaining brain section. We also found that the absolute delta power in the resected area was higher than that in the remaining area. However, this trend was not statistically different in all patients. For relative band powers, we found decreased relative band power in the beta and gamma band ranges within the areas defined by the surgical margins. Delta, theta, and alpha relative band power differences between the resected and remaining areas were inconsistent between the subjects. CONCLUSIONS: Our results showed systematic relative beta and gamma band power variation in the resected areas of LGS patients.

The Impact of a 35-Week Long-Term Exercise Therapy on Psychosocial Health of Children With Benign Epilepsy.

The purpose of this study was to evaluate the feasibility of a 35-week exercise program and its efficacy on neurocognitive and psychological variables in children with benign epilepsy with centrotemporal spikes. Ten children with benign epilepsy with centrotemporal spikes (aged 8 to 12 years) completed a 35-week exercise program consisting of supervised sport activities for 5 weeks and home-based exercise program for 30 weeks. The children and their parents participated in neurocognitive and psychological evaluations including measures of attention, executive function, behaviors, and quality of life at baseline and postexercise follow-up at the 35th week. At postintervention evaluation, significant improvements were seen relative to baseline in neurocognitive domains such as psychomotor speed, sustained attention, divided attention, and inhibition-disinhibition ability, and in psychological domains including internalizing behavior problems, general health, and general quality of life. Long-term exercise intervention may have benefits for some aspects of neurocognitive and psychological function in children with benign epilepsy.

Simultaneous neural and movement recording in large-scale immersive virtual environments.

Virtual reality (VR) allows precise control and manipulation of rich, dynamic stimuli that, when coupled with on-line motion capture and neural monitoring, can provide a powerful means both of understanding brain behavioral relations in the high dimensional world and of assessing and treating a variety of neural disorders. Here we present a system that combines state-of-the-art, fully immersive, 3D, multi-modal VR with temporally aligned electroencephalographic (EEG) recordings. The VR system is dynamic and interactive across visual, auditory, and haptic interactions, providing sight, sound, touch, and force. Crucially, it does so with simultaneous EEG recordings while subjects actively move about a 20 × 20 ft² space. The overall end-to-end latency between real movement and its simulated movement in the VR is approximately 40 ms. Spatial precision of the various devices is on the order of millimeters. The temporal alignment with the neural recordings is accurate to within approximately 1 ms. This powerful combination of systems opens up a new window into brain-behavioral relations and a new means of assessment and rehabilitation of individuals with motor and other disorders.

Anticipatory modulation of digit placement for grasp control is affected by Parkinson's disease.

BACKGROUND: Successful object manipulation relies on the ability to form and retrieve sensorimotor memories of digit forces and positions used in previous object lifts. Past studies of patients affected by Parkinson's disease (PD) have revealed that the basal ganglia play a crucial role in the acquisition and/or retrieval of sensorimotor memories for grasp control. Whereas it is known that PD impairs anticipatory control of digit forces during grasp, learning deficits associated with the planning of digit placement have yet to be explored. This question is motivated by recent work in healthy subjects revealing that anticipatory control of digit placement plays a crucial role for successful manipulation. METHODOLOGY/PRINCIPAL FINDINGS: We asked ten PD patients off medication and ten age-matched controls to reach, grasp and lift an object whose center of mass (CM) was on the left, right or center. The only task requirement was to minimize object roll during lift. The CM remained the same across consecutive trials (blocked condition) or was altered from trial to trial (random condition). We hypothesized that impairment of the basal ganglia-thalamo-cortical circuits in PD patients would reduce their ability to anticipate digit placement appropriate to the CM location. Consequently, we predicted that PD patients would exhibit similar digit placement in the blocked vs. random conditions and produce larger peak object rolls than that of control subjects. In the blocked condition, PD patients exhibited significantly weaker modulation of fingertip contact points to CM location and larger object roll than controls (p<0.05 and p<0.01, respectively). Nevertheless, both controls and PD patients minimized object roll more in the blocked than in the random condition (p<0.01). CONCLUSIONS/SIGNIFICANCE: Our findings indicate that, even though PD patients may have a residual ability of anticipatory control of digit contact points and forces, they fail to implement a motor plan with the same degree of effectiveness as controls. We conclude that intact basal ganglia-thalamo-cortical circuits are necessary for successful sensorimotor learning of both grasp kinematics and kinetics required for dexterous hand-object interactions.