Computational analysis of functional connectivity between areas of primate cerebral cortex

Recent analyses of association fibre networks in the primate cerebral cortex have revealed a small number of densely intra-connected and hierarchically organized structural systems. Corresponding analyses of data on functional connectivity are required to establish the significance of these structural systems. We therefore built up a relational database by systematically collating published data on the spread of activity after strychnine-induced disinhibition in the macaque cerebral cortex in vivo. After mapping these data to two different parcellation schemes, we used three independent methods of analysis which demonstrate that the cortical network of functional interactions is not homogeneous, but shows a clear segregation into functional assemblies of mutually interacting areas. The assemblies suggest a principal division of the cortex into visual, somatomotor and orbito-temporo-insular systems, while motor and somatosensory areas are inseparably interrelated. These results are largely compatible with corresponding analyses of structural data of mammalian cerebral cortex, and deliver the first functional evidence for 'small-world' architecture of primate cerebral cortex.     

Computational Models Describing Possible Mechanisms for Generation of Excessive Beta Oscillations in Parkinson’s Disease

In Parkinson’s disease, an increase in beta oscillations within the basal ganglia nuclei has been shown to be associated with difficulty in movement initiation. An important role in the generation of these oscillations is thought to be played by the motor cortex and by a network composed of the subthalamic nucleus (STN) and the external segment of globus pallidus (GPe). Several alternative models have been proposed to describe the mechanisms for generation of the Parkinsonian beta oscillations. However, a recent experimental study of Tachibana and colleagues yielded results which are challenging for all published computational models of beta generation. That study investigated how the presence of beta oscillations in a primate model of Parkinson’s disease is affected by blocking different connections of the STN-GPe circuit. Due to a large number of experimental conditions, the study provides strong constraints that any mechanistic model of beta generation should satisfy. In this paper we present two models consistent with the data of Tachibana et al. The first model assumes that Parkinsonian beta oscillation are generated in the cortex and the STN-GPe circuits resonates at this frequency. The second model additionally assumes that the feedback from STN-GPe circuit to cortex is important for maintaining the oscillations in the network. Predictions are made about experimental evidence that is required to differentiate between the two models, both of which are able to reproduce firing rates, oscillation frequency and effects of lesions carried out by Tachibana and colleagues. Furthermore, an analysis of the models reveals how the amplitude and frequency of the generated oscillations depend on parameters.     

Growth/differentiation factor 7 is preferentially expressed in the primary motor area of the monkey neocortex

We applied a differential display PCR technique to isolate molecules that are area-specific in expression in the primate neocortex, and found that growth/differentiation factor 7 (GDF7), a member of the bone morphogenetic protein (BMP)/transforming growth factor (TGF) beta super-family, is preferentially expressed in the primary motor area of African green monkeys (Cercopithecus aethiops). We proved that GDF7 is 10 times more abundant in the motor cortex than in the visual cortex by northern blotting and quantitative RT-PCR. When we examined the neocortex of closely related rhesus monkeys (Macaca mulatta), GDF7 was also most abundant in the motor cortex, although the regional difference was reduced to 3-fold. This differential expression pattern was observed in both newborn and infant rhesus monkeys. We found that several type I/II receptors of BMP, candidates of the receptors for GDF7, are uniformly expressed in the mature neocortex. The unique expression pattern of GDF7 suggests that it may play an active role in the motor area of the primate neocortex.     

Different motor learning effects on excitability changes of motor cortex in muscle contraction state

Abstract

We aimed to investigate whether motor learning induces different excitability changes in the human motor cortex (M1) between two different muscle contraction states (before voluntary contraction [static] or during voluntary contraction [dynamic]). For the same, using motor evoked potentials (MEPs) obtained by transcranial magnetic stimulation (TMS), we compared excitability changes during these two states after pinch-grip motor skill learning. The participants performed a force output tracking task by pinch grip on a computer screen. TMS was applied prior to the pinch grip (static) and after initiation of voluntary contraction (dynamic). MEPs of the following muscles were recorded: first dorsal interosseous (FDI), thenar muscle (Thenar), flexor carpi radialis (FCR), and extensor carpi radialis (ECR) muscles. During both the states, motor skill training led to significant improvement of motor performance. During the static state, MEPs of the FDI muscle were significantly facilitated after motor learning; however, during the dynamic state, MEPs of the FDI, Thenar, and FCR muscles were significantly decreased. Based on the results of this study, we concluded that excitability changes in the human M1 are differentially influenced during different voluntary contraction states (static and dynamic) after motor learning.     

Current density threshold for the stimulation of neurons in the motor cortex area

The aim of this study was to determine a current density threshold for exciting the motor cortex area of the brain. The current density threshold for excitation of nerve fibres (20 microm in diameter) found in the literature is approximately 1 A/m(2) at frequencies lower than 1 kHz. In consideration of a safety factor of 100, the International Commission on Non-Ionizing Radiation Protection (ICNIRP) recommends to restrict the exposure to 0.01 A/m(2). The electromagnetic stimulation of neurons in the motor cortex is used in the clinical diagnosis of nerve lesions and neuropathy by means of magnetic or electrical transcranial stimulation. Combining medical data from clinical studies and technical specifications of the Magstim Model 200 stimulator, we were able to compute the current density threshold for the excitation of the human motor cortex by means of the finite element method (FEM). A 3D-CAD head model was built on the basis of magnetic resonance imaging (MRI) slices and segmented into four anatomical structures (scalp, skull, brain, and ventricular system) with different conductivities. A current density threshold for the stimulation of the motor cortex area of the upper limbs of 6 and 2.5 A/m(2) at 2.44 kHz and 50 Hz, respectively, was calculated. As these values lie above the recommended ICNIRP values by two orders of magnitude there is no need for lower safety standards with regard to stimulation of the brain.     

Changes in electrical thresholds for evoking movements from the cat cerebral cortex following lesions of the sensori-motor area

We evaluated motor maps in the cerebral cortex and motor performance in cats before and after lesions of the forelimb representation in the primary motor area. After the lesion there was a reduction in the use of the affected forelimb and loss of accuracy in prehension tasks using the forelimb; some recovery occurred during the mapping study. Electrode tracts and lesion sites were located in cytoarchitectonically identified cortical areas 4γ, 4δ, 6aα, 6aγ, 3a. The lesions were mainly in area 4γ. In the lesioned hemisphere there were many points around the lesion site (in areas 4γ and 3a) from which movements could not be evoked. In some areas distant from the lesion site (e.g. area 6aγ) the mean thresholds for evoking forelimb movements were significantly elevated. Mean thresholds for evoking hindlimb and facial movements were not different from before. In the contralateral hemisphere mean thresholds for evoking forelimb, but not hindlimb or facial movements, were significantly elevated in several sensorimotor areas (area 4γ, 6aγ and 3a). Mean thresholds for evoking forelimb movements appeared to progressively increase during the time of study. Minimal currents required to evoke forelimb movements from the cerebral cortex increase (possibly progressively) following a lesion of the forelimb representation in the primary motor area, affecting many interconnected motor areas in the hemispheres ipsilateral and contralateral to the lesioned site. This increase in thresholds may play a role in the changes in cortical control of the affected and contralateral limbs following brain lesions and explain the increased sense of effort required to produce movements.     

Non-Invasive Electrical Brain Stimulation Montages for Modulation of Human Motor Function

Non-invasive electrical brain stimulation (NEBS) is used to modulate brain function and behavior, both for research and clinical purposes. In particular, NEBS can be applied transcranially either as direct current stimulation (tDCS) or alternating current stimulation (tACS). These stimulation types exert time-, dose- and in the case of tDCS polarity-specific effects on motor function and skill learning in healthy subjects. Lately, tDCS has been used to augment the therapy of motor disabilities in patients with stroke or movement disorders. This article provides a step-by-step protocol for targeting the primary motor cortex with tDCS and transcranial random noise stimulation (tRNS), a specific form of tACS using an electrical current applied randomly within a pre-defined frequency range. The setup of two different stimulation montages is explained. In both montages the emitting electrode (the anode for tDCS) is placed on the primary motor cortex of interest. For unilateral motor cortex stimulation the receiving electrode is placed on the contralateral forehead while for bilateral motor cortex stimulation the receiving electrode is placed on the opposite primary motor cortex. The advantages and disadvantages of each montage for the modulation of cortical excitability and motor function including learning are discussed, as well as safety, tolerability and blinding aspects.     

Functional recovery in a primate model of Parkinson's disease following motor cortex stimulation

A concept in Parkinson's disease postulates that motor cortex may pattern abnormal rhythmic activities in the basal ganglia, underlying the genesis of observed motor symptoms. We conducted a preclinical study of electrical interference in the primary motor cortex using a chronic MPTP primate model in which dopamine depletion was progressive and regularly documented using 18F-DOPA positron tomography. High-frequency motor cortex stimulation significantly reduced akinesia and bradykinesia. This behavioral benefit was associated with an increased metabolic activity in the supplementary motor area as assessed with 18-F-deoxyglucose PET, a normalization of mean firing rate in the internal globus pallidus (GPi) and the subthalamic nucleus (STN), and a reduction of synchronized oscillatory neuronal activities in these two structures. Motor cortex stimulation is a simple and safe procedure to modulate subthalamo-pallido-cortical loop and alleviate parkinsonian symptoms without requiring deep brain stereotactic surgery.     

Dating primate divergences through an integrated analysis of palaeontological and molecular data

Estimation of divergence times is usually done using either the fossil record or sequence data from modern species. We provide an integrated analysis of palaeontological and molecular data to give estimates of primate divergence times that utilize both sources of information. The number of preserved primate species discovered in the fossil record, along with their geological age distribution, is combined with the number of extant primate species to provide initial estimates of the primate and anthropoid divergence times. This is done by using a stochastic forwards-modeling approach where speciation and fossil preservation and discovery are simulated forward in time. We use the posterior distribution from the fossil analysis as a prior distribution on node ages in a molecular analysis. Sequence data from two genomic regions (CFTR on human chromosome 7 and the CYP7A1 region on chromosome 8) from 15 primate species are used with the birth-death model implemented in mcmctree in PAML to infer the posterior distribution of the ages of 14 nodes in the primate tree. We find that these age estimates are older than previously reported dates for all but one of these nodes. To perform the inference, a new approximate Bayesian computation (ABC) algorithm is introduced, where the structure of the model can be exploited in an ABC-within-Gibbs algorithm to provide a more efficient analysis.     

Stimulating the Lip Motor Cortex with Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) has proven to be a useful tool in investigating the role of the articulatory motor cortex in speech perception. Researchers have used single-pulse and repetitive TMS to stimulate the lip representation in the motor cortex. The excitability of the lip motor representation can be investigated by applying single TMS pulses over this cortical area and recording TMS-induced motor evoked potentials (MEPs) via electrodes attached to the lip muscles (electromyography; EMG). Larger MEPs reflect increased cortical excitability. Studies have shown that excitability increases during listening to speech as well as during viewing speech-related movements. TMS can be used also to disrupt the lip motor representation. A 15-min train of low-frequency sub-threshold repetitive stimulation has been shown to suppress motor excitability for a further 15-20 min. This TMS-induced disruption of the motor lip representation impairs subsequent performance in demanding speech perception tasks and modulates auditory-cortex responses to speech sounds. These findings are consistent with the suggestion that the motor cortex contributes to speech perception. This article describes how to localize the lip representation in the motor cortex and how to define the appropriate stimulation intensity for carrying out both single-pulse and repetitive TMS experiments.     

Lateral prefrontal cortex: architectonic and functional organization

A comparison of the architecture of the human prefrontal cortex with that of the macaque monkey showed a very similar architectonic organization in these two primate species. There is no doubt that the prefrontal cortical areas of the human brain have undergone considerable development, but it is equally clear that the basic architectonic organization is the same in the two species. Thus, a comparative approach to the study of the functional organization of the primate prefrontal cortex is more likely to reveal the essential aspects of the various complex control processes that are the domain of frontal function. The lateral frontal cortex appears to be functionally organized along both a rostral-caudal axis and a dorsal-ventral axis. The most caudal frontal region, the motor region on the precentral gyrus, is involved in fine motor control and direct sensorimotor mappings, whereas the caudal lateral prefrontal region is involved in higher order control processes that regulate the selection among multiple competing responses and stimuli based on conditional operations. Further rostrally, the mid-lateral prefrontal region plays an even more abstract role in cognitive control. The mid-lateral prefrontal region is itself organized along a dorsal-ventral axis of organization, with the mid-dorsolateral prefrontal cortex being involved in the monitoring of information in working memory and the mid-ventrolateral prefrontal region being involved in active judgments on information held in posterior cortical association regions that are necessary for active retrieval and encoding of information.     

Brain reorganization,not relative brain size,primarily characterizes anthropoid brain evolution

Comparative analyses of primate brain evolution have highlighted changes in size and internal organization as key factors underlying species diversity. It remains, however, unclear (i) how much variation in mosaic brain reorganization versus variation in relative brain size contributes to explaining the structural neural diversity observed across species, (ii) which mosaic changes contribute most to explaining diversity, and (iii) what the temporal origin, rates and processes are that underlie evolutionary shifts in mosaic reorganization for individual branches of the primate tree of life. We address these questions by combining novel comparative methods that allow assessing the temporal origin, rate and process of evolutionary changes on individual branches of the tree of life, with newly available data on volumes of key brain structures (prefrontal cortex, frontal motor areas and cerebrocerebellum) for a sample of 17 species (including humans). We identify patterns of mosaic change in brain evolution that mirror brain systems previously identified by electrophysiological and anatomical tract-tracing studies in non-human primates and functional connectivity MRI studies in humans. Across more than 40 Myr of anthropoid primate evolution, mosaic changes contribute more to explaining neural diversity than changes in relative brain size, and different mosaic patterns are differentially selected for when brains increase or decrease in size. We identify lineage-specific evolutionary specializations for all branches of the tree of life covered by our sample and demonstrate deep evolutionary roots for mosaic patterns associated with motor control and learning.     

Comparison of electrical thresholds for evoking movements from sensori-motor areas of the cat cerebral cortex and its relation to motor training

Motor maps and electrical thresholds for evoking movements from motor areas of the cerebral cortex were evaluated in normal cats by using intracortical microstimulation techniques. Stainless steel chambers were implanted over craniotomies in adult cats trained to perform reaching and retrieval movements with their forelimbs. Prehensile motor training was continued and movement performance monitored for about 6–10 weeks during which the cortex was progressively explored with sharp tungsten electrodes inserted into cortical gyri (anterior and posterior sigmoid, and coronal) and the banks of sulci (cruciate, presylvian and coronal). Twice weekly, under light general anaesthesia, 3–4 tracks were made in either hemisphere till about 50 tracks were made in each hemisphere. Mean thresholds for evoking forelimb movements from different cytoarchitectonic areas (4γ, 4δ, 6aγ and 3a) were compared and no consistent or significant differences were observed between the different areas. In the animals (4/6) which used either forelimb to perform the tasks, there were no consistent differences in the mean thresholds for evoking forelimb movements from the two hemispheres. However, in 2 animals, which used their right forelimbs predominantly or exclusively to perform all the tasks, mean thresholds for evoking forelimb movements was significantly higher in areas 4γ and 6aγ of the left hemisphere (compared to the right); no consistent differences in the mean thresholds for evoking hindlimb or facial movements were observed between the two hemispheres. These findings suggest that ICMS thresholds for evoking forelimb movements may be similar in different sensorimotor areas of the cat cerebral cortex, and these thresholds could be influenced by motor training.     

Personality research with non-human primates: theoretical formulation and methods

Since the earliest periods of primatology study, researchers have been aware of animals’ consistent individual differences in behavior or personality. Many papers have been published on this subject, but they lacked a common theoretical and methodological background. The present work is an attempt to provide such theoretical and methodological foundations to this field of biological science. In the theoretical formulation section, “biological study of personality” is first derived as an extension of the ethology paradigm, and non-human primate personality research is subsequently characterized as its strategic component. In the methodology section, brief reviews and discussions are presented on subjective and objective personality assessment methods with non-human primates with a reference to the reliability and validity concepts in human psychometrics. The work provides a theoretical framework and methodological suggestions for non-human primate personality research.     

Set-Related Activity in the Premotor Cortex of Rhesus Monkeys: Effect of Triggering Cues and Relatively Long Delay Intervals

“Set-related activity” has been defined as a significant alteration in neuronal discharge rate during an “instructed delay period,” a period when a previously instructed movement is being withheld. It has been argued that set-related activity in the primate premotor cortex, or at least a significant proportion of it, reflects motor preparation. In most previous investigations, however, in which visual stimuli have triggered the movement and simultaneously indicated its target, set-related activity might reflect either the anticipation of or attention to the trigger stimulus. The present report shows that set-related activity is robust and can be directionally selective when trigger stimuli do not indicate the target and when a trigger stimulus is absent. Another feature of previous studies has been the relatively brief intervals between the instruction and trigger stimuli (typically 3 sec or less). In the present study, we were able to observe the activity of a small number of cells during longer delay periods. Set-related activity persists, although it becomes less consistent, for as much as 7.5 sec after an instruction stimulus. These results support the hypothesis that set-related activity reflects the preparation for specific limb movements.     

Representation of movements and muscles within the primate precentral motor cortex: historical and current perspectives

A major problem with the study of the control of movement and posture is to determine how specific brain areas contribute to the selection of those particular muscle patterns that underlie a coordinated movement. With this problem in mind, a selective review is presented of mapping studies of the primate motor cortex, whose results bear on the question of how the spatial organization of cortical efferent cells might contribute to the production of organized muscle synergies. More recent findings are also summarized, which appear to resolve previous controversies on the question of whether movements or muscles are the primary units of motor cortex organization. These same findings suggest also a form of spatial organization within the primate precentral gyrus that would allow spatially simple afferent inputs to evoke the muscle synergies that are necessary for a variety of simple movements of the arm and hand.     

Mapping behavioral repertoire onto the cortex

A traditional view of the motor cortex in the primate brain is that it contains a map of the body arranged across the cortical surface. This traditional topographic scheme, however, does not capture the actual pattern of overlaps, fractures, re-representations, and multiple areas separated by fuzzy borders. Here, we suggest that the organization of the motor cortex, premotor cortex, supplementary motor cortex, frontal eye field, and supplementary eye field can in principle be understood as a best-fit rendering of the motor repertoire onto the two-dimensional cortical sheet in a manner that optimizes local continuity.     

Effect of neuromuscular electrical stimulation on motor cortex excitability upon release of tonic muscle contraction

The aim of the present study was to investigate the neurophysiological triggers underlying muscle relaxation from the contracted state, and to examine the mechanisms involved in this process and their subsequent modification by neuromuscular electrical stimulation (NMES). Single-pulse transcranial magnetic stimulation (TMS) was used to produce motor-evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) in 23 healthy participants, wherein motor cortex excitability was examined at the onset of voluntary muscle relaxation following a period of voluntary tonic muscle contraction. In addition, the effects of afferent input on motor cortex excitability, as produced by NMES during muscle contraction, were examined. In particular, two NMES intensities were used for analysis: 1.2 times the sensory threshold and 1.2 times the motor threshold (MT). Participants were directed to execute constant wrist extensions and to release muscle contraction in response to an auditory “GO” signal. MEPs were recorded from the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles, and TMS was applied at three different time intervals (30, 60, and 90?ms) after the “GO” signal. Motor cortex excitability was greater during voluntary ECR and FCR relaxation using high-intensity NMES, and relaxation time was decreased. Each parameter differed significantly between 30 and 60?ms. Moreover, in both muscles, SICI was larger in the presence than in the absence of NMES. Therefore, the present findings suggest that terminating a muscle contraction triggers transient neurophysiological mechanisms that facilitate the NMES-induced modulation of cortical motor excitability in the period prior to muscle relaxation. High-intensity NMES might facilitate motor cortical excitability as a function of increased inhibitory intracortical activity, and therefore serve as a transient trigger for the relaxation of prime mover muscles in a therapeutic context.     

A Sensorimotor Model for Computing Intended Reach Trajectories

The presumed role of the primate sensorimotor system is to transform reach targets from retinotopic to joint coordinates for producing motor output. However, the interpretation of neurophysiological data within this framework is ambiguous, and has led to the view that the underlying neural computation may lack a well-defined structure. Here, I consider a model of sensorimotor computation in which temporal as well as spatial transformations generate representations of desired limb trajectories, in visual coordinates. This computation is suggested by behavioral experiments, and its modular implementation makes predictions that are consistent with those observed in monkey posterior parietal cortex (PPC). In particular, the model provides a simple explanation for why PPC encodes reach targets in reference frames intermediate between the eye and hand, and further explains why these reference frames shift during movement. Representations in PPC are thus consistent with the orderly processing of information, provided we adopt the view that sensorimotor computation manipulates desired movement trajectories, and not desired movement endpoints.     

Lesions to primary sensory and posterior parietal cortices impair recovery from hand paresis after stroke

Background

Neuroanatomical determinants of motor skill recovery after stroke are still poorly understood. Although lesion load onto the corticospinal tract is known to affect recovery, less is known about the effect of lesions to cortical sensorimotor areas. Here, we test the hypothesis that lesions of somatosensory cortices interfere with the capacity to recover motor skills after stroke.

Methods

Standardized tests of motor skill and somatosensory functions were acquired longitudinally over nine months in 29 patients with stroke to the pre- and postcentral gyrus, including adjacent areas of the frontal, parietal and insular cortices. We derived the recovery trajectories of each patient for five motor subtest using least-squares curve fitting and objective model selection procedures for linear and exponential models. Patients were classified into subgroups based on their motor recovery models. Lesions were mapped onto diffusion weighted imaging scans and normalized into stereotaxic space using cost-function masking. To identify critical neuranatomical regions, voxel-wise subtractions were calculated between subgroup lesion maps. A probabilistic cytoarchitectonic atlas was used to quantify of lesion extent and location.

Results

Twenty-three patients with moderate to severe initial deficits showed exponential recovery trajectories for motor subtests that relied on precise distal movements. Those that retained a chronic motor deficit had lesions that extended to the center of the somatosensory cortex (area 2) and the intraparietal sulcus (areas hIP1, hIP2). Impaired recovery outcome correlated with lesion extent on this areas and somatosensory performance. The rate of recovery, however, depended on the lesion load onto the primary motor cortex (areas 4a, 4p).

Conclusions

Our findings support a critical role of uni-and multimodal somatosensory cortices in motor skill recovery. Whereas lesions to these areas influence recovery outcome, lesions to the primary motor cortex affect recovery dynamics. This points to a possible dissociation of neural substrates for different aspects of post-stroke recovery.