Activation of human primary motor cortex during action observation: A neuromagnetic study

The monkey premotor cortex contains neurons that discharge during action execution and during observation of actions made by others. Transcranial magnetic stimulation experiments suggest that a similar observation/execution matching system also is present in humans. We recorded neuromagnetic oscillatory activity of the human precentral cortex from 10 healthy volunteers while (i) they had no task to perform, (ii) they were manipulating a small object, and (iii) they were observing another individual performing the same task. The left and right median nerves were stimulated alternately (interstimulus interval, 1.5 s) at intensities exceeding motor threshold, and the poststimulus rebound of the rolandic 15- to 25-Hz activity was quantified. In agreement with previous studies, the rebound was strongly suppressed bilaterally during object manipulation. Most interestingly, the rebound also was significantly diminished during action observation (31–46% of the suppression during object manipulation). Control experiments, in which subjects were instructed to observe stationary or moving stimuli, confirmed the specificity of the suppression effect. Because the recorded 15- to 25-Hz activity is known to originate mainly in the precentral motor cortex, we concluded that the human primary motor cortex is activated during observation as well as execution of motor tasks. These findings have implications for a better understanding of the machinery underlying action recognition in humans.

Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia

Antipsychotic drug treatment of schizophrenia may be complicated by side effects of widespread dopaminergic antagonism, including exacerbation of negative and cognitive symptoms due to frontal cortical hypodopaminergia. Atypical antipsychotics have been shown to enhance frontal dopaminergic activity in animal models. We predicted that substitution of risperidone for typical antipsychotic drugs in the treatment of schizophrenia would be associated with enhanced functional activation of frontal cortex. We measured cerebral blood oxygenation changes during periodic performance of a verbal working memory task, using functional MRI, on two occasions (baseline and 6 weeks later) in two cohorts of schizophrenic patients. One cohort (n = 10) was treated with typical antipsychotic drugs throughout the study. Risperidone was substituted for typical antipsychotics after baseline assessment in the second cohort (n = 10). A matched group of healthy volunteers (n = 10) was also studied on a single occasion. A network comprising bilateral dorsolateral prefrontal and lateral premotor cortex, the supplementary motor area, and posterior parietal cortex was activated by working memory task performance in both the patients and comparison subjects. A two-way analysis of covariance was used to estimate the effect of substituting risperidone for typical antipsychotics on power of functional response in the patient group. Substitution of risperidone increased functional activation in right prefrontal cortex, supplementary motor area, and posterior parietal cortex at both voxel and regional levels of analysis. This study provides direct evidence for significantly enhanced frontal function in schizophrenic patients after substitution of risperidone for typical antipsychotic drugs, and it indicates the potential value of functional MRI as a tool for longitudinal assessment of psychopharmacological effects on cerebral physiology.

Forebrain mechanisms of nociception and pain: Analysis through imaging

Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

Optical imaging of functional domains in the cortex of the awake and behaving monkey

As demonstrated by anatomical and physiological studies, the cerebral cortex consists of groups of cortical modules, each comprising populations of neurons with similar functional properties. This functional modularity exists in both sensory and association neocortices. However, the role of such cortical modules in perceptual and cognitive behavior is unknown. To aid in the examination of this issue we have applied the high spatial resolution optical imaging methodology to the study of awake, behaving animals. In this paper, we report the optical imaging of orientation domains and blob structures, approximately 100–200 μm in size, in visual cortex of the awake and behaving monkey. By overcoming the spatial limitations of other existing imaging methods, optical imaging will permit the study of a wide variety of cortical functions at the columnar level, including motor and cognitive functions traditionally studied with positron-emission tomography or functional MRI techniques.

Functional organization of spatial and nonspatial working memory processing within the human lateral frontal cortex

The present study used functional magnetic resonance imaging to demonstrate that performance of visual spatial and visual nonspatial working memory tasks involve the same regions of the lateral prefrontal cortex when all factors unrelated to the type of stimulus material are appropriately controlled. These results provide evidence that spatial and nonspatial working memory may not be mediated, respectively, by mid-dorsolateral and mid-ventrolateral regions of the frontal lobe, as widely assumed, and support the alternative notion that specific regions of the lateral prefrontal cortex make identical executive functional contributions to both spatial and nonspatial working memory.

Synchronization between prefrontal and posterior association cortex during human working memory

We measured coherence between the electroencephalogram at different scalp sites while human subjects performed delayed response tasks. The tasks required the retention of either verbalizable strings of characters or abstract line drawings. In both types of tasks, a significant enhancement in coherence in the θ range (4–7 Hz) was found between prefrontal and posterior electrodes during 4-s retention intervals. During 6-s perception intervals, far fewer increases in θ coherence were found. Also in other frequency bands, coherence increased; however, the patterns of enhancement made a relevance for working memory processes seem unlikely. Our results suggest that working memory involves synchronization between prefrontal and posterior association cortex by phase-locked, low frequency (4–7 Hz) brain activity.

Bidirectional, experience-dependent regulation of N-methyl-d-aspartate receptor subunit composition in the rat visual cortex during postnatal development

In the visual cortex, as elsewhere, N-methyl-d-aspartate receptors (NMDARs) play a critical role in triggering long-term, experience-dependent synaptic plasticity. Modifications of NMDAR subunit composition alter receptor function, and could have a large impact on the properties of synaptic plasticity. We have used immunoblot analysis to investigate the effects of age and visual experience on the expression of different NMDAR subunits in synaptoneurosomes prepared from rat visual cortices. NMDARs at birth are comprised of NR2B and NR1 subunits, and, over the first 5 postnatal weeks, there is a progressive inclusion of the NR2A subunit. Dark rearing from birth attenuates the developmental increase in NR2A. Levels of NR2A increase rapidly (in <2 hr) when dark-reared animals are exposed to light, and decrease gradually over the course of 3 to 4 days when animals are deprived of light. These data reveal that NMDAR subunit composition in the visual cortex is remarkably dynamic and bidirectionally regulated by sensory experience. We propose that NMDAR subunit regulation is a mechanism for experience-dependent modulation of synaptic plasticity in the visual cortex, and serves to maintain synaptic strength within an optimal dynamic range.

Excitatory–inhibitory network in the visual cortex: Psychophysical evidence

At early stages in visual processing cells respond to local stimuli with specific features such as orientation and spatial frequency. Although the receptive fields of these cells have been thought to be local and independent, recent physiological and psychophysical evidence has accumulated, indicating that the cells participate in a rich network of local connections. Thus, these local processing units can integrate information over much larger parts of the visual field; the pattern of their response to a stimulus apparently depends on the context presented. To explore the pattern of lateral interactions in human visual cortex under different context conditions we used a novel chain lateral masking detection paradigm, in which human observers performed a detection task in the presence of different length chains of high-contrast-flanked Gabor signals. The results indicated a nonmonotonic relation of the detection threshold with the number of flankers. Remote flankers had a stronger effect on target detection when the space between them was filled with other flankers, indicating that the detection threshold is caused by dynamics of large neuronal populations in the neocortex, with a major interplay between excitation and inhibition. We considered a model of the primary visual cortex as a network consisting of excitatory and inhibitory cell populations, with both short- and long-range interactions. The model exhibited a behavior similar to the experimental results throughout a range of parameters. Experimental and modeling results indicated that long-range connections play an important role in visual perception, possibly mediating the effects of context.

Glial reduction in the subgenual prefrontal cortex in mood disorders

Mood disorders are among the most common neuropsychiatric illnesses, yet little is known about their neurobiology. Recent neuroimaging studies have found that the volume of the subgenual part of Brodmann’s area 24 (sg24) is reduced in familial forms of major depressive disorder (MDD) and bipolar disorder (BD). In this histological study, we used unbiased stereological techniques to examine the cellular composition of area sg24 in two different sets of brains. There was no change in the number or size of neurons in area sg24 in mood disorders. In contrast, the numbers of glia were reduced markedly in both MDD and BD. The reduction in glial number was most prominent in subgroups of subjects with familial MDD (24%, P = 0.01) or BD (41%, P = 0.01). The glial reduction in subjects without a clear family history was lower in magnitude and not statistically significant. Consistent with neuroimaging findings, cortical volume was reduced in area sg24 in subjects with familial mood disorders. Schizophrenic brains studied as psychiatric controls had normal neuronal and glial numbers and cortical volume. Glial and neuronal numbers also were counted in area 3b of the somatosensory cortex in the same group of brains and were normal in all psychiatric groups. Glia affect several processes, including regulation of extracellular potassium, glucose storage and metabolism, and glutamate uptake, all of which are crucial for normal neuronal activity. We thus have identified a biological marker associated with familial mood disorders that may provide important clues regarding the pathogenesis of these common psychiatric conditions.

Visual stimuli induce waves of electrical activity in turtle cortex

The computations involved in the processing of a visual scene invariably involve the interactions among neurons throughout all of visual cortex. One hypothesis is that the timing of neuronal activity, as well as the amplitude of activity, provides a means to encode features of objects. The experimental data from studies on cat [Gray, C. M., Konig, P., Engel, A. K. & Singer, W. (1989) Nature (London) 338, 334–337] support a view in which only synchronous (no phase lags) activity carries information about the visual scene. In contrast, theoretical studies suggest, on the one hand, the utility of multiple phases within a population of neurons as a means to encode independent visual features and, on the other hand, the likely existence of timing differences solely on the basis of network dynamics. Here we use widefield imaging in conjunction with voltage-sensitive dyes to record electrical activity from the virtually intact, unanesthetized turtle brain. Our data consist of single-trial measurements. We analyze our data in the frequency domain to isolate coherent events that lie in different frequency bands. Low frequency oscillations (<5 Hz) are seen in both ongoing activity and activity induced by visual stimuli. These oscillations propagate parallel to the afferent input. Higher frequency activity, with spectral peaks near 10 and 20 Hz, is seen solely in response to stimulation. This activity consists of plane waves and spiral-like waves, as well as more complex patterns. The plane waves have an average phase gradient of ≈π/2 radians/mm and propagate orthogonally to the low frequency waves. Our results show that large-scale differences in neuronal timing are present and persistent during visual processing.

Brain activity in visual cortex predicts individual differences in reading performance

The relationship between brain activity and reading performance was examined to test the hypothesis that dyslexia involves a deficit in a specific visual pathway known as the magnocellular (M) pathway. Functional magnetic resonance imaging was used to measure brain activity in dyslexic and control subjects in conditions designed to preferentially stimulate the M pathway. Dyslexics showed reduced activity compared with controls both in the primary visual cortex and in a secondary cortical visual area (MT+) that is believed to receive a strong M pathway input. Most importantly, significant correlations were found between individual differences in reading rate and brain activity. These results support the hypothesis for an M pathway abnormality in dyslexia and imply a strong relationship between the integrity of the M pathway and reading ability.

Inputs to directionally selective simple cells in macaque striate cortex

It is clear that the initial analysis of visual motion takes place in the striate cortex, where directionally selective cells are found that respond to local motion in one direction but not in the opposite direction. Widely accepted motion models postulate as inputs to directional units two or more cells whose spatio-temporal receptive fields (RFs) are approximately 90° out of phase (quadrature) in space and in time. Simple cells in macaque striate cortex differ in their spatial phases, but evidence is lacking for the varying time delays required for two inputs to be in temporal quadrature. We examined the space-time RF structure of cells in macaque striate cortex and found two subpopulations of (nondirectional) simple cells, some that show strongly biphasic temporal responses, and others that are weakly biphasic if at all. The temporal impulse responses of these two classes of cells are very close to 90° apart, with the strongly biphasic cells having a shorter latency than the weakly biphasic cells. A principal component analysis of the spatio-temporal RFs of directionally selective simple cells shows that their RFs could be produced by a linear combination of two components; these two components correspond closely in their respective latencies and biphasic characters to those of strongly biphasic and weakly biphasic nondirectional simple cells, respectively. This finding suggests that the motion system might acquire the requisite temporal quadrature by combining inputs from these two classes of nondirectional cells (or from their respective lateral geniculate inputs, which appear to be from magno and parvo lateral geniculate cells, respectively).

Memory fields of neurons in the primate prefrontal cortex

Many prefrontal (PF) neurons convey information about both an object’s identity (what) and its location (where). To explore how they represent conjunctions of what and where, we explored the receptive fields of their mnemonic activity (i.e., their “memory fields”) by requiring monkeys to remember both an object and its location at many positions throughout a wide portion of central vision. Many PF neurons conveyed object information and had highly localized memory fields that emphasized the contralateral, but not necessarily foveal, visual field. These results indicate that PF neurons can simultaneously convey precise location and object information and thus may play a role in constructing a unified representation of a visual scene.

Patches of synchronized activity in the cerebellar cortex evoked by mossy-fiber stimulation: Questioning the role of parallel fibers

The discrepancy between the structural longitudinal organization of the parallel-fiber system in the cerebellar cortex and the functional mosaic-like organization of the cortex has provoked controversial theories about the flow of information in the cerebellum. We address this issue by characterizing the spatiotemporal organization of neuronal activity in the cerebellar cortex by using optical imaging of voltage-sensitive dyes in isolated guinea-pig cerebellum. Parallel-fiber stimulation evoked a narrow beam of activity, which propagated along the parallel fibers. Stimulation of the mossy fibers elicited a circular, nonpropagating patch of synchronized activity. These results strongly support the hypothesis that a beam of parallel fibers, activated by a focal group of granule cells, fails to activate the Purkinje cells along most of its length. It is thus the ascending axon of the granule cell, and not its parallel branches, that activates and defines the basic functional modules of the cerebellar cortex.

Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics

The relative abundance of alternatively spliced long (γ2L) and short (γ2S) mRNAs of the γ2 subunit of the γ-amino butyrate type A (GABAA) receptor was examined in dorsolateral prefrontal cortex of schizophrenics and matched controls by using in situ hybridization histochemistry and semiquantitative reverse transcription–PCR (RT-PCR) amplification. A cRNA probe identifying both mRNAs showed that the transcripts are normally expressed at moderately high levels in the prefrontal cortex. Consistent with previous studies, overall levels of γ2 transcripts in prefrontal cortex of brains from schizophrenics were reduced by 28.0%, although this reduction did not reach statistical significance. RT-PCR, performed under nonsaturating conditions on total RNA from the same blocks of tissue used for in situ hybridization histochemistry, revealed a marked reduction in the relative proportion of γ2S transcripts in schizophrenic brains compared with controls. In schizophrenics, γ2S transcripts had fallen to 51.7% (±7.9% SE; P < 0.0001) relative to control levels. Levels of γ2L transcripts showed only a small and nonsignificant reduction of 16.9% (±12.0% SE, P > 0.05). These findings indicate differential transcriptional regulation of two functionally distinct isoforms of one of the major GABAA receptor subunits in the prefrontal cortex of schizophrenics. The specific reduction in relative abundance of γ2S mRNAs and the associated relative increase in γ2L mRNAs should result in functionally less active GABAA receptors and have severe consequences for cortical integrative function.