Lack of somatotopy among corticospinal tract fibers passing through the primate craniovertebral junction and cervical spinal cord: pathoanatomical substrate of central cord syndrome and cruciate paralysis.

OBJECTIVE: In some cases of incomplete cervical spinal cord injury (iSCI) there is marked paresis and dysfunction of upper-extremity movement but not lower-extremity movement. A continued explanation of such symptoms is a somatotopic organization of corticospinal tract (CST) fibers passing through the decussation at the craniovertebral junction (CVJ) and lateral CST (LCST). In central cord syndrome, it has been suggested that injury to the core of the cervical cord may include selective damage to medially located arm/hand LCST fibers, without compromising laterally located leg fibers. Because such somatotopic organization in the primate CST might contribute to the disproportionate motor deficits after some forms of iSCI, the authors made a systematic investigation of CST organization in the CVJ and LCST using modern neuroanatomical techniques. METHODS: High-resolution anterograde tracers were used in 11 rhesus macaque monkeys to define the course of the corticospinal projection (CSP) through the CVJ and LCST from the arm/hand, shoulder, and leg areas of the primary motor cortex (M1). This approach labels CST fibers of all sizes, large and small, arising in these areas. The CSP from the dorsolateral and ventrolateral premotor cortex and supplementary motor area were also studied. A stereological approach was adapted to quantify labeled fiber distribution in 8 cases. RESULTS: There was no evidence for somatotopic organization of CST fibers passing through the CVJ or contralateral LCST. Fiber labeling from each cortical representation was widespread throughout the CST at the CVJ and LCST and overlapped extensively with fibers from other representations. This study demonstrated no significant difference between medial versus lateral subsectors of the LCST in terms of number of fibers labeled from the M1 arm/hand area. CONCLUSIONS: This investigation firmly rejects the concept of somatotopy among CST fibers passing through the CVJ and LCST, in contrast with the somatotopy in the cortex, corona radiata, and internal capsule. All CST fibers in the CVJ and LCST would thus appear to be equally susceptible to focal or diffuse injury, regardless of their cortical origin. The disproportionate impairment of arm/hand movement after iSCI must therefore be due to other factors, including greater dependence of hand/arm movements on the CST compared with the lower limb. The dispersed and intermingled nature of frontomotor fibers may be important in motor recovery after cervical iSCI.

Classification of Cortical Neurons by Spike Shape and the Identification of Pyramidal Neurons.

Many investigators who make extracellular recordings from populations of cortical neurons are now using spike shape parameters, and particularly spike duration, as a means of classifying different neuronal sub-types. Because of the nature of the experimental approach, particularly that involving nonhuman primates, it is very difficult to validate directly which spike characteristics belong to particular types of pyramidal neurons and interneurons, as defined by modern histological approaches. This commentary looks at the way antidromic identification of pyramidal cells projecting to different targets, and in particular, pyramidal tract neurons (PTN), can inform the utility of spike width classification. Spike duration may provide clues to a diversity of function across the pyramidal cell population, and also highlights important differences that exist across species. Our studies suggest that further electrophysiological and optogenetic approaches are needed to validate spike duration as a means of cell classification and to relate this to well-established histological differences in neocortical cell types.

Movement initiation and grasp representation in premotor and primary motor cortex mirror neurons.

Pyramidal tract neurons (PTNs) within macaque rostral ventral premotor cortex (F5) and (M1) provide direct input to spinal circuitry and are critical for skilled movement control. Contrary to initial hypotheses, they can also be active during action observation, in the absence of any movement. A population-level understanding of this phenomenon is currently lacking. We recorded from single neurons, including identified PTNs, in (M1) (n = 187), and F5 (n = 115) as two adult male macaques executed, observed, or withheld (NoGo) reach-to-grasp actions. F5 maintained a similar representation of grasping actions during both execution and observation. In contrast, although many individual M1 neurons were active during observation, M1 population activity was distinct from execution, and more closely aligned to NoGo activity, suggesting this activity contributes to withholding of self-movement. M1 and its outputs may dissociate initiation of movement from representation of grasp in order to flexibly guide behaviour.

Pattern of paresis in ALS is consistent with the physiology of the corticomotoneuronal projections to different muscle groups.

OBJECTIVE: A recent neuroanatomical staging scheme of amyotrophic lateral sclerosis (ALS) indicates that a cortical lesion may spread, as a network disorder, both at the cortical level and via corticofugal tracts, including corticospinal projections providing direct monosynaptic input to α-motoneurons. These projections are involved preferentially and early in ALS. If these findings are clinically relevant, the pattern of paresis in ALS should primarily involve those muscle groups that receive the strongest direct corticomotoneuronal (CM) innervation. METHODS: In a large cohort (N=436), we analysed retrospectively the pattern of muscle paresis in patients with ALS using the UK Medical Research Council (MRC) scoring system; we subsequently carried out two independent prospective studies in two smaller groups (N=92 and N=54). RESULTS: The results indicated that a characteristic pattern of paresis exists. When pairs of muscle groups were compared within patients, the group known to receive the more pronounced CM connections was significantly weaker. Within patients, there was greater relative weakness (lower MRC score) in thumb abductors versus elbow extensors, for hand extensors versus hand flexors and for elbow flexors versus elbow extensors. In the lower limb, knee flexors were relatively weaker than extensors, and plantar extensors were weaker than plantar flexors. CONCLUSIONS: These findings were mostly significant (p<0.01) for all six pairs of muscles tested and provide indirect support for the concept that ALS may specifically affect muscle groups with strong CM connections. This specific pattern could help to refine clinical and electrophysiological ALS diagnostic criteria and complement prospective clinicopathological correlation studies.

Tractography-based parcellation does not provide strong evidence of anatomical organisation within the thalamus.

Connectivity-based parcellation of subcortical structures using diffusion tractography is now a common paradigm in neuroscience. These analyses often imply voxel-level specificity of connectivity, and the formation of compact, spatially coherent clusters is often taken as strong imaging-based evidence for anatomically distinct subnuclei in an individual. In this study, we demonstrate that internal structure in diffusion anisotropy is not necessary for a plausible parcellation to be obtained, by spatially permuting diffusion parameters within the thalami and repeating the parcellation. Moreover, we show that, in a winner-takes-all paradigm, most voxels receive the same label before and after this shuffling process-a finding that is stable across image acquisitions and tractography algorithms. We therefore suggest that such parcellations should be interpreted with caution.

The Corticospinal Discrepancy: Where are all the Slow Pyramidal Tract Neurons?

This feature article focuses on the discrepancy between the distribution of axon diameters within the primate corticospinal tract, determined neuroanatomically, and the distribution of axonal conduction velocities within the same tract, determined electrophysiologically. We point out the importance of resolving this discrepancy for a complete understanding of corticospinal functions, and discuss the various explanations for the mismatch between anatomy and physiology.

Starting and stopping movement by the primate brain.

We review the current knowledge about the part that motor cortex plays in the preparation and generation of movement, and we discuss the idea that corticospinal neurons, and particularly those with cortico-motoneuronal connections, act as 'command' neurons for skilled reach-to-grasp movements in the primate. We also review the increasing evidence that it is active during processes such as action observation and motor imagery. This leads to a discussion about how movement is inhibited and stopped, and the role in these for disfacilitation of the corticospinal output. We highlight the importance of the non-human primate as a model for the human motor system. Finally, we discuss the insights that recent research into the monkey motor system has provided for translational approaches to neurological diseases such as stroke, spinal injury and motor neuron disease.

Expression of Kv3.1b potassium channel is widespread in macaque motor cortex pyramidal cells: A histological comparison between rat and macaque.

There are substantial differences across species in the organization and function of the motor pathways. These differences extend to basic electrophysiological properties. Thus, in rat motor cortex, pyramidal cells have long duration action potentials, while in the macaque, some pyramidal neurons exhibit short duration "thin" spikes. These differences may be related to the expression of the fast potassium channel Kv3.1b, which in rat interneurons is associated with generation of thin spikes. Rat pyramidal cells typically lack these channels, while there are reports that they are present in macaque pyramids. Here we made a systematic, quantitative comparison of the Kv3.1b expression in sections from macaque and rat motor cortex, using two different antibodies (NeuroMab, Millipore). As our standard reference, we examined, in the same sections, Kv3.1b staining in parvalbumin-positive interneurons, which show strong Kv3.1b immunoreactivity. In macaque motor cortex, a large sample of pyramidal neurons were nearly all found to express Kv3.1b in their soma membranes. These labeled neurons were identified as pyramidal based either by expression of SMI32 (a pyramidal marker), or by their shape and size, and lack of expression of parvalbumin (a marker for some classes of interneuron). Large (Betz cells), medium, and small pyramidal neurons all expressed Kv3.1b. In rat motor cortex, SMI32-postive pyramidal neurons expressing Kv3.1b were very rare and weakly stained. Thus, there is a marked species difference in the immunoreactivity of Kv3.1b in pyramidal neurons, and this may be one of the factors explaining the pronounced electrophysiological differences between rat and macaque pyramidal neurons.

Scene-selective coding by single neurons in the human parahippocampal cortex.

Imaging, electrophysiological, and lesion studies have shown a relationship between the parahippocampal cortex (PHC) and the processing of spatial scenes. Our present knowledge of PHC, however, is restricted to the macroscopic properties and dynamics of bulk tissue; the behavior and selectivity of single parahippocampal neurons remains largely unknown. In this study, we analyzed responses from 630 parahippocampal neurons in 24 neurosurgical patients during visual stimulus presentation. We found a spatially clustered subpopulation of scene-selective units with an associated event-related field potential. These units form a population code that is more distributed for scenes than for other stimulus categories, and less sparse than elsewhere in the medial temporal lobe. Our electrophysiological findings provide insight into how individual units give rise to the population response observed with functional imaging in the parahippocampal place area.

Modulation of the Intracortical LFP during Action Execution and Observation.

The activity of mirror neurons in macaque ventral premotor cortex (PMv) and primary motor cortex (M1) is modulated by the observation of another's movements. This modulation could underpin well documented changes in EEG/MEG activity indicating the existence of a mirror neuron system in humans. Because the local field potential (LFP) represents an important link between macaque single neuron and human noninvasive studies, we focused on mirror properties of intracortical LFPs recorded in the PMv and M1 hand regions in two macaques while they reached, grasped and held different objects, or observed the same actions performed by an experimenter. Upper limb EMGs were recorded to control for covert muscle activity during observation.The movement-related potential (MRP), investigated as intracortical low-frequency LFP activity (<9 Hz), was modulated in both M1 and PMv, not only during action execution but also during action observation. Moreover, the temporal LFP modulations during execution and observation were highly correlated in both cortical areas. Beta power in both PMv and M1 was clearly modulated in both conditions. Although the MRP was detected only during dynamic periods of the task (reach/grasp/release), beta decreased during dynamic and increased during static periods (hold).Comparison of LFPs for different grasps provided evidence for partially nonoverlapping networks being active during execution and observation, which might be related to different inputs to motor areas during these conditions. We found substantial information about grasp in the MRP corroborating its suitability for brain-machine interfaces, although information about grasp was generally low during action observation.

Single-cell responses to face adaptation in the human medial temporal lobe.

We used a face adaptation paradigm to bias the perception of ambiguous images of faces and study how single neurons in the human medial temporal lobe (MTL) respond to the same images eliciting different percepts. The ambiguous images were morphs between the faces of two familiar individuals, chosen because at least one MTL neuron responded selectively to one but not to the other face. We found that the firing of MTL neurons closely followed the subjects' perceptual decisions--i.e., recognizing one person or the other. In most cases, the response to the ambiguous images was similar to the one obtained when showing the pictures without morphing. Altogether, these results show that many neurons in the medial temporal lobe signal the subjects' perceptual decisions rather than the visual features of the stimulus.

Influence of spiking activity on cortical local field potentials.

The intra-cortical local field potential (LFP) reflects a variety of electrophysiological processes including synaptic inputs to neurons and their spiking activity. It is still a common assumption that removing high frequencies, often above 300 Hz, is sufficient to exclude spiking activity from LFP activity prior to analysis. Conclusions based on such supposedly spike-free LFPs can result in false interpretations of neurophysiological processes and erroneous correlations between LFPs and behaviour or spiking activity. Such findings might simply arise from spike contamination rather than from genuine changes in synaptic input activity. Although the subject of recent studies, the extent of LFP contamination by spikes is unclear, and the fundamental problem remains. Using spikes recorded in the motor cortex of the awake monkey, we investigated how different factors, including spike amplitude, duration and firing rate, together with the noise statistic, can determine the extent to which spikes contaminate intra-cortical LFPs. We demonstrate that such contamination is realistic for LFPs with a frequency down to ∼10 Hz. For LFP activity below ∼10 Hz, such as movement-related potential, contamination is theoretically possible but unlikely in real situations. Importantly, LFP frequencies up to the (high-) gamma band can remain unaffected. This study shows that spike-LFP crosstalk in intra-cortical recordings should be assessed for each individual dataset to ensure that conclusions based on LFP analysis are valid. To this end, we introduce a method to detect and to visualise spike contamination, and provide a systematic guide to assess spike contamination of intra-cortical LFPs.

M1 corticospinal mirror neurons and their role in movement suppression during action observation.

Evidence is accumulating that neurons in primary motor cortex (M1) respond during action observation, a property first shown for mirror neurons in monkey premotor cortex. We now show for the first time that the discharge of a major class of M1 output neuron, the pyramidal tract neuron (PTN), is modulated during observation of precision grip by a human experimenter. We recorded 132 PTNs in the hand area of two adult macaques, of which 65 (49%) showed mirror-like activity. Many (38 of 65) increased their discharge during observation (facilitation-type mirror neuron), but a substantial number (27 of 65) exhibited reduced discharge or stopped firing (suppression-type). Simultaneous recordings from arm, hand, and digit muscles confirmed the complete absence of detectable muscle activity during observation. We compared the discharge of the same population of neurons during active grasp by the monkeys. We found that facilitation neurons were only half as active for action observation as for action execution, and that suppression neurons reversed their activity pattern and were actually facilitated during execution. Thus, although many M1 output neurons are active during action observation, M1 direct input to spinal circuitry is either reduced or abolished and may not be sufficient to produce overt muscle activity.

The activity of primary motor cortex corticospinal neurons during tool use by macaque monkeys.

It has been suggested that the distinctive capacity of some nonhuman primates to use tools may reflect a well-developed corticospinal system and, in particular, direct cortico-motoneuronal (CM) connections to hand muscles. We investigated the activity of corticospinal neurons in the primary motor cortex hand area during the use of a tool by two adult macaque monkeys. They used a light rake to retrieve food rewards placed in their extrapersonal space. An analysis of EMG activity showed that the rake task involved a complex interaction of muscles acting on the digits, hand, and arm. Sixty-nine corticospinal neurons were identified antidromically as pyramidal tract neurons (PTNs). When tested on the rake task, most (64 of 69; 93%) showed a significant modulation of their discharge during at least one of three task periods: grasping the rake, projecting it beyond the food reward, and then pulling it back to retrieve the reward. Discharge patterns were heterogeneous, and many PTNs showed significant suppression of discharge during raking. Seventeen of the 69 PTNs recorded during the rake task were further identified as CM cells, exerting clear postspike facilitation on digit muscles, demonstrating that the CM system contributes to the skilled use of tools. We compared the activity of each PTN on the rake task with that during precision grip. Most PTNs (90%) modulated their activity significantly for both tasks, demonstrating that PTNs activated by a task involving fractionated movements of the digits are also recruited during rake use, although there were often contrasting patterns of PTN recruitment and muscle activity for the two tasks.

Large identified pyramidal cells in macaque motor and premotor cortex exhibit "thin spikes": implications for cell type classification.

Recent studies have suggested that extracellular recordings of putative cortical interneurons have briefer spikes than those of pyramidal neurons, providing a means of identifying cortical cell types in recordings from awake monkeys. To test this, we investigated the spike duration of antidromically identified pyramidal tract neurons (PTNs) recorded from primary motor (M1) or ventral premotor cortex (area F5) in 4 awake macaque monkeys. M1 antidromic latencies (ADLs) were skewed toward short ADLs (151 PTNs; 0.5-5.5 ms, median 1.1 ms) and significantly different from that of F5 ADLs (54 PTNs; 1.0-6.9 ms, median 2.6 ms). The duration of PTN spikes, recorded with a high-pass filter of 300 Hz and measured from the negative trough to the positive peak of the spike waveform, ranged from 0.15 to 0.71 ms. Importantly, we found a positive linear correlation between ADL and spike duration in both M1 (R(2) = 0.40, p < 0.001) and F5 (R(2) = 0.57, p < 0.001). Thus PTNs with the shortest ADL (fastest axons) had the briefest spikes, and since PTN soma size is correlated with axon size and conduction velocity, it is likely that the largest pyramidal neurons (Betz cells in M1) have spikes with short durations (0.15-0.45 ms), which overlap heavily with those reported for putative interneurons in previous studies in non-primates. In summary, one class of physiologically identified cortical pyramidal neuron exhibits a wide variety of spike durations and the results suggest that spike duration alone may not be a reliable indicator of cell type.

A category-specific response to animals in the right human amygdala.

The amygdala is important in emotion, but it remains unknown whether it is specialized for certain stimulus categories. We analyzed responses recorded from 489 single neurons in the amygdalae of 41 neurosurgical patients and found a categorical selectivity for pictures of animals in the right amygdala. This selectivity appeared to be independent of emotional valence or arousal and may reflect the importance that animals held throughout our evolutionary past.

Ventral premotor-motor cortex interactions in the macaque monkey during grasp: response of single neurons to intracortical microstimulation.

Recent stimulation studies in monkeys and humans have shown strong interactions between ventral premotor cortex (area F5) and the hand area of primary motor cortex (M1). These short-latency interactions usually involve facilitation from F5 of M1 outputs to hand muscles, although suppression has also been reported. This study, performed in three awake macaque monkeys, sought evidence that these interactions could be mediated by short-latency excitatory and inhibitory responses of single M1 neurons active during grasping tasks. We recorded responses of these M1 neurons to single low-threshold (≤40 µA) intracortical microstimuli delivered to F5 sites at which grasp-related neurons were recorded. In 29 sessions, we tested 232 M1 neurons with stimuli delivered to between one and four sites in F5. Of the 415 responses recorded, 142 (34%) showed significant effects. The most common type of response was pure excitation (53% of responses), with short latency (1.8-3.0 ms) and brief duration (∼1 ms); purely inhibitory responses had slightly longer latencies (2-5 ms) and were of small amplitude and longer duration (5-7 ms). They accounted for 13% of responses, whereas mixed excitation then inhibition was seen in 34%. Remarkably, a rather similar set of findings applied to 280 responses of 138 F5 neurons to M1 stimulation; 109 (34%) responses showed significant effects. Thus, with low-intensity stimuli, the dominant interaction between these two cortical areas is one of short-latency, brief excitation, most likely mediated by reciprocal F5-M1 connections. Some neurons were tested with stimuli at both 20 and 40 µA; inhibition tended to dominate at the higher intensity.

Interactions between areas of the cortical grasping network.

Skilled grasp is a sensorimotor process requiring the brain to extract sensory cues from the environment to shape a motor command. Although a large body of literature has focused on which brain areas either integrate the visual object's properties or control the motor output, it is still unclear how grasp-related information is transferred from one area to another. Understanding interactions between brain areas is crucial for the study of visuomotor transformations. Recently, new advances in both human and non-human primates have shown it is possible to study cortico-cortical interactions during different task contexts. This sheds new light on how brain areas are integrated in a dynamic network for controlling grasping actions.

On-line, voluntary control of human temporal lobe neurons.

Daily life continually confronts us with an exuberance of external, sensory stimuli competing with a rich stream of internal deliberations, plans and ruminations. The brain must select one or more of these for further processing. How this competition is resolved across multiple sensory and cognitive regions is not known; nor is it clear how internal thoughts and attention regulate this competition. Recording from single neurons in patients implanted with intracranial electrodes for clinical reasons, here we demonstrate that humans can regulate the activity of their neurons in the medial temporal lobe (MTL) to alter the outcome of the contest between external images and their internal representation. Subjects looked at a hybrid superposition of two images representing familiar individuals, landmarks, objects or animals and had to enhance one image at the expense of the other, competing one. Simultaneously, the spiking activity of their MTL neurons in different subregions and hemispheres was decoded in real time to control the content of the hybrid. Subjects reliably regulated, often on the first trial, the firing rate of their neurons, increasing the rate of some while simultaneously decreasing the rate of others. They did so by focusing onto one image, which gradually became clearer on the computer screen in front of their eyes, and thereby overriding sensory input. On the basis of the firing of these MTL neurons, the dynamics of the competition between visual images in the subject's mind was visualized on an external display.