Fast Compensatory Functional Network Changes Caused by Reversible Inactivation of Monkey Parietal Cortex.

The brain has a remarkable capacity to recover after lesions. However, little is known about compensatory neural adaptations at the systems level. We addressed this question by investigating behavioral and (correlated) functional changes throughout the cortex that are induced by focal, reversible inactivations. Specifically, monkeys performed a demanding covert spatial attention task while the lateral intraparietal area (LIP) was inactivated with muscimol and whole-brain fMRI activity was recorded. The inactivation caused LIP-specific decreases in task-related fMRI activity. In addition, these local effects triggered large-scale network changes. Unlike most studies in which animals were mainly passive relative to the stimuli, we observed heterogeneous effects with more profound muscimol-induced increases of task-related fMRI activity in areas connected to LIP, especially FEF. Furthermore, in areas such as FEF and V4, muscimol-induced changes in fMRI activity correlated with changes in behavioral performance. Notably, the activity changes in remote areas did not correlate with the decreased activity at the site of the inactivation, suggesting that such changes arise via neuronal mechanisms lying in the intact portion of the functional task network, with FEF a likely key player. The excitation-inhibition dynamics unmasking existing excitatory connections across the functional network might initiate these rapid adaptive changes.

Selective TMS-induced modulation of functional connectivity correlates with changes in behavior.

Despite the increasing use of functional connectivity (FC) studies in fundamental and clinical research, the link between FC and behavior is still poorly understood. To test the hypothesis that artificial modulation of FC correlates with changes in behavior in a quantitative manner, we performed behavioral and resting state fMRI experiments in monkeys while perturbing, offline, the frontal eye fields (FEF) using unilateral continuous theta burst transcranial magnetic stimulation (FEF-cTBS). Stimulation of left and right FEF caused remarkably specific decreases in FC, which were symmetric for intra-hemispheric and asymmetric for inter-hemispheric FC. Surprisingly, FEF-cTBS improved the performance and compensated intrinsic choice biases in saccadic behavior of four monkeys, independent of the initial bias direction. Moreover, the direction of the stimulation-induced effects on both behavior (i.e. bias compensation) and FC (i.e. decrease) were independent of the stimulated hemisphere, while their magnitude depended on the side of stimulation, choice bias and monkey. Overall, the naturally-occurring saccade biases determined the FC changes following FEF-cTBS. Finally, we showed that the average decreases in FC in the FEF network induced by cTBS can be used to predict, with high specificity, both the direction (opposite to the saccadic biases) and the magnitude of the shift in saccadic choice preference relative to the unperturbed state. To reconcile the apparent contradiction between improved performance and bias compensation vs. decrease in functional connectivity, we propose that the main functional consequences of FEF-cTBS relate to adjusting inter-hemispheric imbalances.

Optogenetics in primates: a shining future?

To understand the functional role of specific neurons in micro- and macro-brain circuitry, health, and disease, it is critical to control their activity precisely. This ambitious goal was first achieved by optogenetics, allowing researchers to increase or decrease neural activity artificially with high temporal and spatial precision. In contrast to the revolution optogenetics engendered in invertebrate and rodent research, only a few studies have reported optogenetic-induced neuronal and behavioral effects in primates. Such studies are nonetheless critical before optogenetics can be applied in a clinical setting. Here, we review the state-of-the-art tools for performing optogenetics in mammals, emphasizing recent neuronal and behavioral results obtained in nonhuman primates.

Evidence for cross-modal plasticity in adult mouse visual cortex following monocular enucleation.

The goal of this study was to assess cortical reorganization in the visual system of adult mice in detail. A combination of deprivation of one eye and stimulation of the remaining eye previously led to the identification of input-specific subdivisions in mouse visual cortex. Using this information as a reference map, we established to what extent each of these functional subdivisions take part in cortical reactivation and reorganization upon unilateral enucleation. A recovery experiment revealed a differential laminar and temporal reactivation profile. Initiation of infragranular recovery of molecular activity near the border with nonvisual cortex and simultaneous hyperactivation of this adjacent cortex implied a partial nonvisual contribution to this plasticity. The strong effect of somatosensory deprivation as well as stimulation on infragranular visual cortex activation in long-term enucleated animals support this view. Furthermore, targeted tracer injections in visual cortex of control and enucleated animals revealed preexisting connections between the visual and somatosensory cortices of adult mice as possible mediators. In conclusion, this study supports an important cross-modal component in reorganization of adult mouse visual cortex upon monocular enucleation.

Transcranial magnetic stimulation of macaque frontal eye fields decreases saccadic reaction time.

Transcranial magnetic stimulation (TMS) is increasingly used to perturb targeted human brain sites non-invasively, to test for causal effects on performance of cognitive tasks. TMS might also be used in non-human primates to complement invasive work and compare with human studies. Here, we targeted the frontal eye fields (FEF) in two macaques with a continuous theta-burst (cTBS) protocol, testing the impact on visually guided saccades. After unilateral cTBS over the FEF in either hemisphere, a small (mean 7 ms) but highly consistent decrease in saccadic reaction times (RTs) was observed. Lower latencies arose for saccades both contra- and ipsilateral to the stimulated FEF after cTBS. These results provide the first demonstration that TMS can be used to affect saccadic behavior in non-human primates. The unexpectedly bilateral impact on RTs may reflect an impact on 'fixation' neurons in the FEF and/or transcallosal modulation of both FEFs induced by unilateral cTBS. In either case, this study demonstrates a clear behavioral effect induced by TMS in awake behaving monkeys performing a cognitive task. This opens new opportunities for investigating the causal roles of targeted brain areas in behavior, for measuring physiological consequences of TMS in the primate brain, and ultimately for human-monkey comparisons.

Serotype-dependent transduction efficiencies of recombinant adeno-associated viral vectors in monkey neocortex.

Viral vector-mediated expression of genes (e.g., coding for opsins and designer receptors) has grown increasingly popular. Cell-type specific expression is achieved by altering viral vector tropism through crosspackaging or by cell-specific promoters driving gene expression. Detailed information about transduction properties of most recombinant adeno-associated viral vector (rAAV) serotypes in macaque cortex is gradually becoming available. Here, we compare transduction efficiencies and expression patterns of reporter genes in two macaque neocortical areas employing different rAAV serotypes and promoters. A short version of the calmodulin-kinase-II (CaMKIIα0.4) promoter resulted in reporter gene expression in cortical neurons for all tested rAAVs, albeit with different efficiencies for spread: rAAV2/5>>rAAV2/7>rAAV2/8>rAAV2/9>>rAAV2/1 and proportion of transduced cells: rAAV2/1>rAAV2/5>rAAV2/7=rAAV2/9>rAAV2/8. In contrast to rodent studies, the cytomegalovirus (CMV) promoter appeared least efficient in macaque cortex. The human synapsin-1 promoter preceded by the CMV enhancer (enhSyn1) produced homogeneous reporter gene expression across all layers, while two variants of the CaMKIIα promoter resulted in different laminar transduction patterns and cell specificities. Finally, differences in expression patterns were observed when the same viral vector was injected in two neocortical areas. Our results corroborate previous findings that reporter-gene expression patterns and efficiency of rAAV transduction depend on serotype, promoter, cortical layer, and area.

A practical application of text mining to literature on cognitive rehabilitation and enhancement through neurostimulation.

The exponential growth in publications represents a major challenge for researchers. Many scientific domains, including neuroscience, are not yet fully engaged in exploiting large bodies of publications. In this paper, we promote the idea to partially automate the processing of scientific documents, specifically using text mining (TM), to efficiently review big corpora of publications. The "cognitive advantage" given by TM is mainly related to the automatic extraction of relevant trends from corpora of literature, otherwise impossible to analyze in short periods of time. Specifically, the benefits of TM are increased speed, quality and reproducibility of text processing, boosted by rapid updates of the results. First, we selected a set of TM-tools that allow user-friendly approaches of the scientific literature, and which could serve as a guide for researchers willing to incorporate TM in their work. Second, we used these TM-tools to obtain basic insights into the relevant literature on cognitive rehabilitation (CR) and cognitive enhancement (CE) using transcranial magnetic stimulation (TMS). TM readily extracted the diversity of TMS applications in CR and CE from vast corpora of publications, automatically retrieving trends already described in published reviews. TMS emerged as one of the important non-invasive tools that can both improve cognitive and motor functions in numerous neurological diseases and induce modulations/enhancements of many fundamental brain functions. TM also revealed trends in big corpora of publications by extracting occurrence frequency and relationships of particular subtopics. Moreover, we showed that CR and CE share research topics, both aiming to increase the brain's capacity to process information, thus supporting their integration in a larger perspective. Methodologically, despite limitations of a simple user-friendly approach, TM served well the reviewing process.

Clinical value of echocardiographic Doppler-derived right ventricular dp/dt in patients with pulmonary arterial hypertension.

AIMS: Right ventricular (RV) dp/dt is the instantaneous rate of RV pressure rise during early systole and is a surrogate marker of RV contractility. The main objective of this study was to evaluate the ability of echocardiographic Doppler obtained RV dp/dt to predict long-term survival in patients with pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: Seventy-eight consecutive newly diagnosed untreated patients (64 ± 15 years, 71% female, 57% PAH, 43% inoperable CTEPH) were included in the study. At baseline, patients were assessed clinically [New York Heart Association (NYHA) and 6 minutes walking distance (6MWD)], by transthoracic cardiac ultrasound and by right heart catherization. RV dp/dt was assessed using spectral Doppler recordings from the tricuspid regurgitation signal at a sweep speed of 200 mm/s by measuring the time interval in which the regurgitant velocity increased from 0.5 to 2 m/s. During a mean follow-up period of 3.5 ± 1.7 years, 31 patients died and 3 received a lung transplant [study endpoint reached in 34/78 (44%) patients]. The optimal RV dp/dt cut-off was determined by receiver operating characteristic analysis at 3 years to be 410 mmHg/s (specificity 84%, positive-predictive value 55%, and negative-predictive value 83%). In univariate analysis, RV dp/dt <410 mmHg/s (hazard ratio 2.67, 95% CI 1.30-5.47, P = 0.007), tricuspid annulus plane systolic excursion (TAPSE) <15 mm, NYHA, 6MWD, and right atrial pressure were predictors of mortality. In a multivariate model with TAPSE, RV dp/dt remained an independent predictor of mortality (P = 0.01). CONCLUSION: A reduced baseline RV dp/dt is a clear indicator of poor outcome independent of TAPSE in patients with PAH/CTEPH.

Optogenetically induced behavioral and functional network changes in primates.

Optogenetics is currently the state-of-the-art method for causal-oriented brain research. Despite an increasingly large number of invertebrate and rodent studies showing profound electrophysiological and behavioral effects induced by optogenetics, only two primate studies have reported modulation of local single-cell activity but with no behavioral effects. Here, we show that optogenetic stimulation of cortical neurons within rhesus monkey arcuate sulcus, during the execution of a visually guided saccade task, evoked significant and reproducible changes in saccade latencies as a function of target position. Moreover, using concurrent optogenetic stimulation and opto-fMRI), we observed optogenetically induced changes in fMRI activity in specific functional cortical networks throughout the monkey brain. This is critical information for the advancement of optogenetic primate research models and for initiating the development of optogenetically based cell-specific therapies with which to treat neurological diseases in humans.

Identification and localization of functional subdivisions in the visual cortex of the adult mouse.

We investigated the anatomical characteristics of the mouse visual system through in situ hybridization for the neuronal activity marker zif268. Our main goal was to delineate the full extent of the cortical region processing visual information and additionally to identify the monocularly and binocularly driven subregions therein. We therefore analyzed the neocortex of monocularly and binocularly enucleated mice versus visually stimulated control mice. These visual manipulations revealed eye-specific parcellations at the neocortical level. In binocularly enucleated mice we detected an unambiguous lateral border between visually driven and nonvisual cortex based on the clear deprivation-induced reduction in zif268 expression in the first. However, medially a transition zone of intermediate intensity was found between primarily visual, that is V1 and multimodal retrosplenial cortex. Also in monocularly enucleated mice, the visual cortex contralateral to the deprived eye clearly displayed distinct regions of lower signal than the ipsilateral cortex. Yet interspersed between these regions of basal activity we could clearly identify a zone of high activity spanning the V1-V2L border. A second zone of higher activity was noticeable near the medial border of visual cortex. Comparison with binocularly enucleated mice indicates the presence of both binocular input as well as nonvisual input in this medial cortical region and thus confirms the transitional nature of the recently described rostromedial areas.