Julien Vezoli

Visual areas exert feedforward and feedback influences through distinct frequency channels

Visual cortical areas subserve cognitive functions by interacting in both feedforward and feedback directions. While feedforward influences convey sensory signals, feedback influences modulate feedforward signaling according to the current behavioral context. We investigated whether these interareal influences are subserved differentially by rhythmic synchronization. We correlated frequency-specific directed influences among 28 pairs of visual areas with anatomical metrics of the feedforward or feedback character of the respective interareal projections. This revealed that in the primate visual system, feedforward influences are carried by theta-band (∼ 4 Hz) and gamma-band (∼ 60-80 Hz) synchronization, and feedback influences by beta-band (∼ 14-18 Hz) synchronization. The functional directed influences constrain a functional hierarchy similar to the anatomical hierarchy, but exhibiting task-dependent dynamic changes in particular with regard to the hierarchical positions of frontal areas. Our results demonstrate that feedforward and feedback signaling use distinct frequency channels, suggesting that they subserve differential communication requirements.

A Weighted and Directed Interareal Connectivity Matrix for Macaque Cerebral Cortex

Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation <1 log unit, range 5 log units). The connectivity profile for each area conformed to a lognormal distribution, where a majority of projections are moderate or weak in strength. In the G29 × 29 interareal subgraph, two-thirds of the connections that can exist do exist. Analysis of the smallest set of areas that collects links from all 91 nodes of the G29 × 91 subgraph (dominating set analysis) confirms the dense (66%) structure of the cortical matrix. The G29 × 29 subgraph suggests an unexpectedly high incidence of unidirectional links. The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans. It will also inform future modeling studies that explore the regularities of cortical networks.

Alpha-Beta and Gamma Rhythms Subserve Feedback and Feedforward Influences among Human Visual Cortical Areas.

Primate visual cortex is hierarchically organized. Bottom-up and top-down influences are exerted through distinct frequency channels, as was recently revealed in macaques by correlating inter-areal influences with laminar anatomical projection patterns. Because this anatomical data cannot be obtained in human subjects, we selected seven homologous macaque and human visual areas, and we correlated the macaque laminar projection patterns to human inter-areal directed influences as measured with magnetoencephalography. We show that influences along feedforward projections predominate in the gamma band, whereas influences along feedback projections predominate in the alpha-beta band. Rhythmic inter-areal influences constrain a functional hierarchy of the seven homologous human visual areas that is in close agreement with the respective macaque anatomical hierarchy. Rhythmic influences allow an extension of the hierarchy to 26 human visual areas including uniquely human brain areas. Hierarchical levels of ventral- and dorsal-stream visual areas are differentially affected by inter-areal influences in the alpha-beta band.

Communication through coherence with inter-areal delays.

The communication-through-coherence (CTC) hypothesis proposes that anatomical connections are dynamically rendered effective or ineffective through the presence or absence of rhythmic synchronization, in particular in the gamma and beta bands. The original CTC statement proposed that uni-directional communication is due to rhythmic entrainment with an inter-areal delay and a resulting non-zero phase relation, whereas bi-directional communication is due to zero-phase synchronization. Recent studies found that inter-areal gamma-band synchronization entails a non-zero phase lag. We therefore modify the CTC hypothesis and propose that bi-directional cortical communication is realized separately for the two directions by uni-directional CTC mechanisms entailing delays in both directions. We review evidence suggesting that inter-areal influences in the feedforward and feedback directions are segregated both anatomically and spectrally.

Frontal Feedback-Related Potentials in Nonhuman Primates: Modulation during Learning and under Haloperidol

Feedback monitoring and adaptation of performance involve a medial reward system including medial frontal cortical areas, the medial striatum, and the dopaminergic system. A considerable amount of data has been obtained on frontal surface feedback-related potentials (FRPs) in humans and on the correlate of outcome monitoring with single unit activity in monkeys. However, work is needed to bridge knowledge obtained in the two species. The present work describes FRPs in monkeys, using chronic recordings, during a trial and error task. We show that frontal FRPs are differentially sensitive to successes and failures and can be observed over long-term periods. In addition, using the dopamine antagonist haloperidol we observe a selective effect on FRP amplitude that is absent for pure sensory-related potentials. These results describe frontal dopaminergic-dependent FRPs in monkeys and corroborate a human-monkey homology for performance monitoring signals.

The Effects of Cognitive Control and Time on Frontal Beta Oscillations

Frontal beta oscillations are associated with top-down control mechanisms but also change over time during a task. It is unclear whether change over time represents another control function or a neural instantiation of vigilance decrements over time, the time-on-task effect. We investigated how frontal beta oscillations are modulated by cognitive control and time. We used frontal chronic electrocorticography in monkeys performing a trial-and-error task, comprising search and repetition phases. Specific beta oscillations in the delay period of each trial were modulated by task phase and adaptation to feedback. Beta oscillations in this same period showed a significant within-session change. These separate modulations of beta oscillations did not interact. Crucially, and in contrast to previous investigations, we examined modulations of beta around spontaneous pauses in work. After pauses, the beta power modulation was reset and the cognitive control effect was maintained. Cognitive performance was also maintained whereas behavioral signs of fatigue continued to increase. We propose that these beta oscillations reflect multiple factors contributing to the regulation of cognitive control. Due to the effect of pauses, the time-sensitive factor cannot be a neural correlate of time-on-task but may reflect attentional effort.

Recombinant Proteins to Induce Pluripotent Stem Cells: Promises for a Safer and Thriving Step Toward Clinical Trials

Embryonic stem cells (ESCs) offer an unlimited source of replacement material for regenerative medicine to potentially treat many disabling diseases, including PD, or other neurodegenerative conditions. However, using ESCs for cellular therapy raises a number of ethical and medical problems, as their production requires the destruction of human embryos and allograft necessitates immunosuppressive treatment. To overcome these problems, the recent technology of induced pluripotent stem cells (iPSCs) allows the reprogramming of adult somatic cells into genuine pluripotent stem cells by introducing four main genes (Oct4, Sox2, Klf4, and cMyc) into their genome. iPSCs have become a tool for the development of cellular therapy techniques because they permit autologous transplantation, thus obviating problems associated with immunosuppressive treatment. Although holding great promise for personalized regenerative medicine, one crucial aspect is the genetic integrity of iPSCs. Indeed, viral vectors were used, at first, to introduce reprogramming genes that are irreversibly integrated and may induce uncontrolled proliferation of transplanted cells until tumor formation. Over 3 years, iPSCs research has expanded exponentially, and new virus-free methods have been developed to induce pluripotency (e.g., excising introduced exogenous genes to remove vector traces from iPSCs genome or using nonintegrative recombinant proteins). Recently, Rhee et al. published an elegant study (J Clin Invest DOI: 10.1172/JCI45794) comparing differentiation and cellular properties of lentivirus-, retrovirus-, and protein-based human iPSCs to human ESCs. Optimized coculture and fine selection methods lead to the efficient generation of neural precursor cells (NPCs) and dopaminergic (DA) neurons from all iPSC lines; however, virus-based iPSCs presented limited expansion and early senescence, compared to protein-based and ESCs. Moreover, residual expression of exogenous genes was observed in virus-based, but not in protein-based, iPSCs. In the face of these results, the investigators selected the safer line for therapeutic in vivo application in a rodent model of PD. NPC grafts into the striatum resulted in striking behavioral recovery associated with a high proportion of THþ neurons, although tumor generation was observed when a high concentration of NPCs was grafted. Importantly, the results also confirmed that fully differentiated DA neurons are too vulnerable to survive transplantation, as no functional recovery and no THþ neurons were observed in this case. This study elegantly showed the superiority of virus-free iPSCs, although further optimization is still needed to remove residual undifferentiated cells and associated tumor risk. Such work should pave the way for standardized quality control before moving iPSCs into clinical trials.

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives

Abstract In order to calibrate stem cell exploitation for cellular therapy in neurodegenerative diseases, fundamental and preclinical research in NHP (nonhuman primate) models is crucial. Indeed, it is consensually recognized that it is not possible to directly extrapolate results obtained in rodent models to human patients. A large diversity of neurological pathologies should benefit from cellular therapy based on neural differentiation of stem cells. In the context of this special issue of Primate Biology on NHP stem cells, we describe past and recent advances on cell replacement in the NHP model of Parkinsons disease (PD). From the different grafting procedures to the various cell types transplanted, we review here diverse approaches for cell-replacement therapy and their related therapeutic potential on behavior and function in the NHP model of PD.