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Cortical hyperexcitability is cortical under-inhibition: evidence from a novel functional test of migraine patients.

Recent studies of the visual cortex in patients with migraine have generally concluded that migraine (particularly migraine with aura) is associated with a state of functional cortical hyperexcitability. The mechanisms giving rise to this hyperexcitability have hitherto been unclear. This paper reports two studies that used a novel investigative technique, derived from basic research in vision science, to examine specific deficits of inhibitory processing in primary visual cortex. The technique is termed the metacontrast test, and it examines visual masking under highly specified conditions. In Study 1, 12 migraine with aura patients (MA), 12 age-matched migraine without aura patients (MO) and 12 age- and sex-matched headache-free control subjects (C) were compared using the metacontrast test. MA patients were significantly less susceptible to visual masking in the metacontrast test than both MO and C groups: this result is highly consistent with a deficit in cortical inhibitory processing in MA patients. Study 2 examined MA patients taking a variety of migraine prophylactics, again using the metacontrast test. Test results normalized in those MA patients taking sodium valproate, but not in those taking other prophylactics. Sodium valproate is a GABA-A agonist that is known to cross the blood-brain barrier: GABA-ergic networks act as the primary inhibitory mechanism in visual cortex. Taken together, the results of these studies argue that cortical hyperexcitability, at least in MA patients, is likely to be a result of deficient intracortical inhibitory processes.

Adult↗

The postnatal growth of the callosal connections of primary and secondary visual cortex in the rat.

The growth of callosal projections is completed earlier in primary than in secondary visual cortex. In area 17, the areal and laminar distributions of callosal projections are mature by days 9 and 12, respectively, whereas in area 18b, these developmental milestones occur by days 12 and 15, respectively. This suggests that the pruning and infiltration of callosal axons follow different schedules in different cortical areas.

Animals↗

Adjacent visual cortical complex cells share about 20% of their stimulus-related information.

The responses of adjacent neurons in inferior temporal (IT) cortex carry signals that are to a large degree independent (Gawne and Richmond, 1993). Adjacent primary visual cortical neurons have similar orientation tuning (Hubel and Wiesel, 1962, 1968), suggesting that their responses might be more redundant than those in IT. We recorded the responses of 26 pairs of adjacent complex cells in the primary visual cortex of two awake monkeys while using both a set of 16 bar-like stimuli, and a more complex set of 128 two-dimensional patterns. Linear regression showed that 40% of the signal variance of one neuron was related to that of the other when the responses to the bar-like stimuli were considered. However, when the responses to the two-dimensional stimuli were included in the analysis, only 19% of the signal variance of one neuron was related to that of the adjacent one, almost exactly the same results as found in IT. An information theoretic analysis gave similar results. We hypothesize that this trend toward independence of information processing by adjacent cortical neurons is a general organizational strategy used to maximize the amount of information carried in local groups.

Action Potentials↗

Variation in the cortical area map of C57BL/6J and DBA/2J inbred mice predicts strain identity.

BACKGROUND: Recent discoveries suggest that arealization of the mammalian cortical sheet develops in a manner consonant with principles established for embryonic patterning of the body. Signaling centers release morphogens that determine regional growth and tissue identity by regulating regional expression of transcription factors. Research on mouse cortex has identified several candidate morphogens that affect anteroposterior or mediolateral cortical regionalization as well as mitogenesis. Inbred strains of laboratory mice can be exploited to study cortical area map formation if there are significant phenotypic differences with which to correlate gene polymorphism or expression data. Here we describe differences in the cortical area map of two commonly used inbred strains of laboratory mice, C57BL/6J and DBA/2J. Complete cortical hemispheres from adult mice were dissected and stained for the cytochrome oxidase enzyme in order to measure histochemically defined cortical areas. RESULTS: C57BL/6J has the larger neocortex, relatively larger primary visual cortex (V1), but relatively smaller posterior medial barrel subfield of the primary somatosensory cortex (PMBSF). The sample of C57BL/6J and DBA/2J mice can be discriminated with 90% accuracy on the basis of these three size dimensions. CONCLUSION: C57BL/6J and DBA/2J have markedly different cortical area maps, suggesting that inbred strains harbor enough phenotypic variation to encourage a forward genetic approach to understanding cortical development, complementing other approaches.

Animals↗

Acute effects of lithium on dopaminergic responses: iontophoretic studies in the rat visual cortex.

The interactions between lithium and cortical dopaminergic receptors were investigated using the iontophoretic technique to record and apply dopaminergic compounds, GABA, acetylcholine and LiCl on neurons in the primary visual cortex of the rat. The main responses to dopamine (DA) or to the D1 agonist (+/- )SKF38393 on spontaneously-active (SA) or visually-driven (VD) units was a prolonged decrease in firing and a reduction in the responsiveness to pulses of acetylcholine. The D1 antagonist SCH23390, applied iontophoretically or intravenously, blocked or attenuated the inhibitory responses to both DA and (+/- )SKF38393. The D2 agonist quinpirole (LY171555) either produced only slight excitations or had no effects on both VD and SA units. The concomitant application of lithium blocked the inhibitory responses to DA and to (+/- )SKF38393 but did not modify the responsiveness to LY171555. In addition, the DA- and (+/- )SKF38393-induced decreases in responsiveness to acetylcholine were also suppressed by lithium. These effects were on dopaminergic mechanisms, since the excitatory responses to acetylcholine alone as well as the inhibitions caused by GABA were unchanged by the application of lithium. These results imply that the modifications in sensitivity to dopaminergic agents induced by lithium are mediated by dopamine D1 receptors and are discussed in relation to adenylate-cyclase.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Disinhibition as a mechanism for visual cortex neurons to tune to cross-shaped figures.

A discrete simulation model of a receptive field selectively responding to cross-shaped figures, as seen in 40% of primary visual cortex neurons in the cat, was studied. The model was based on disinhibition of end-stop inhibition in the receptive field by the lateral disinhibition zone. These experiments showed that this mechanism can produce selective or, conversely, invariant tuning to the shape and orientation of cross-shaped figures and could underlie the high sensitivity of neurons to second-order image features.

Animals↗

[Functional and structural abnormalities in the visual cortex in early childhood strabismus].

BACKGROUND: To investigate the structural basis for functional deficits in infantile strabismus we used a neuroanatomic tracer and a histochemical label to examine the primary visual cortex (area V1) of adult esotropic macaque monkeys. ANIMALS AND METHODS: The animals had developed natural esotropia in the first months of life, alternated fixation, and exhibited the ocular motor signs that typify strabismus with onset in infancy. After behavioral and VEP testing, ocular dominance columns (ODCs) in V1 were injected with a neuronal traser and labeled for cytochrome oxidase activity. RESULTS: The strabismic monkeys showed striking deficits in binocular luminance visually-evoked potentials (VEPs) and characteristic directional asymmetries in motion VEPs. Binocular horizontal connections between ODCs were reduced an average of 50-60% in strabismic as compared to normal monkeys. ODCs also showed unequal metabolic activity with contralaterally (i.e. nasal retina) driven ODCs showing greater activity in each V1. DISCUSSION AND CONCLUSION: The maldevelopment of connections in upper V1 layers correlates with the abnormalities in binocular and motion VEPs. The unequal metabolic activity suggests interocular suppression. These results provide the first neuroanatomic evidence for cerebral cortex maldevelopments in natural infantile esotropia.

Animals↗

[Glutaminergic hypothesis of schizophrenia: clinical research studies with ketamine].

Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in schizophrenia pathophysiology. Post-mortem studies have revealed a lower density of glutamatergic receptors in patients with schizophrenia. Other studies of cerebrospinal fluid reported lower levels of glutamate in patients with schizophrenia in healthy comparison subjects. The most compelling evidence is provided by the psychomimetic effects of the NMDA antagonists phencyclidine and ketamine. Recently, much interest has been given to the study related to the role of NMDA receptor in pathophysiology of schizophrenia by administration of sub-anesthetic doses of ketamine. A phencyclidine hydrochloride derivate, ketamine, is a dissociative anesthetic and a non competitive antagonist of the NMDA receptor. In healthy subjects, ketamine produces: 1) positive symptoms of psychosis, such as illusions, thought disorder and delusions; 2) negative symptoms similar to those associated with schizophrenia including blunted emotional responses, emotional detachment, and psychomotor retardation; 3) cognitive impairments, in particular impairments on tests of frontal cortical function including increased distractibility, reduced verbal fluency and poorer performance on the Wisconsin Card Sorting Test. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities which are among the characteristics of schizophrenia. In patients with schizophrenia, the administration of ketamine produces an activation of their psychotic symptoms, which have striking similarities to symptoms of their usual psychotic episodes. Ketamine effects on memory and other cognitive functions in schizophrenic patients are controversial. The psychomimetic effects of ketamine are transitional, reversible and influenced by time, dose and administration conditions. Susceptibility to the psychotomimetic effects of ketamine is minimal or absent in children and becomes maximal in early adulthood. The similarity between ketamine effects and endogenous psychoses created interest in the capacity of antipsychotic medications to block ketamine effects. Haloperidol failed to block this ketamine-induced psychomimetic effects in healthy subjects and in schizophrenic patients. However, clozapine, the prototype of atypical antipsychotic agents significantly reduced the ketamine-induced increase in positive symptoms in schizophrenic patients. Recently, lamotrigine significantly decreased ketamine-induced positive and negative symptoms in healthy subjects. Brain regions responsible for NMDA-mediated psychosis have not been established. Using positron emission tomography and [18F] fluorodeoxyglucose, the sub-anesthetic ketamine administration produces bilateral increases in metabolic activity in the prefrontal cortex. In a [15O] H2O positron emission tomography study, ketamine selectively increases cerebral blood flow in the anterior cingulate cortex and reduces cerebral blood flow in the hippocampus and primary visual cortex. The mechanism of neuropsychiatric effects of sub-anesthetic ketamine is not clear. A dysfunction in glutamate-dopaminergic interactions has been suggested as a mechanism for these effects of ketamine. Ketamine has been reported to primarily block NMDA receptor complex giving support to a glutamate deficiency hypothesis in schizophrenia. In addition, ketamine caused increases in cortical and striatal synaptic dopamine concentrations. The effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Pharmacological modulation of the effects of NMDA receptor antagonists, such as ketamine, may lead to development of novel therapeutic agents for psychiatric illnesses such as schizophrenia.

Brain↗

Does laminar position determine the receptive field properties of cortical neurons? A study of corticotectal cells in area 17 of the normal mouse and the reeler mutant.

The neocortex of the reeler (rl) mutant mouse develops abnormally; as a result, the orderly arrangement of cells in laminae containing neurons of similar size and configuration is severely disrupted. The reeler mutant thus offers an opportunity to study the role played by laminar position in establishing the interneuronal connections of the cortex. Since the receptive field properties of neurons in the primary visual cortex (area 17) are determined by these complex interconnections, a study of receptive field properties provides a useful way to test whether functionally important connections are altered by abnormal cell position. We chose the corticotectal (CT) cells of area 17 for this analysis because they have distinctive receptive field properties and can be identified positively by antidromic stimulation with electrodes in the superior colliculus. In addition, CT cells are located in a single lamina (layer V) in the visual cortex of normal mice, but are distributed from surface to white matter in the reeler visual cortex. We characterized the receptive fields of identified CT cells in area 17 of normal mice and reeler mutants and studied several properties of these cells quantitatively. Corticotectal cells in the visual cortex of the normal mouse have high rates of spontaneous activity and large receptive fields that are neither oriented nor directional; they respond to moving stimuli over a wide range of stimulus velocities, have high peak velocity sensitivities, and show very little spatial summation. Corticotectal cells in the visual cortex of the reeler mutant do not differ significantly in these characteristics, although CT cells with extremely large receptive fields are encountered somewhat more frequently in reeler cortex. These findings indicate that the detailed connections which determine the receptive field properties of CT cells are properly established in the reeler mutant mouse despite the markedly abnormal positions of CT cells in reeler visual cortex.

Animals↗

Comparison of hemodynamic response nonlinearity across primary cortical areas.

Hemodynamic responses to auditory and visual stimuli and motor tasks were assessed for the nonlinearity of response in each of the respective primary cortices. Five stimulus or task durations were used (1, 2, 4, 8, and 16 s), and five male subjects (aged 19 +/- 1.9 years) were imaged. Two tests of linearity were conducted. The first test consisted of using BOLD responses to short stimuli to predict responses to longer stimuli. The second test consisted of fitting ideal impulse response functions to the observed responses for each event duration. Both methods show that the extent of the nonlinearity varies across cortices. Results for the second method indicate that the hemodynamic response is nonlinear for stimuli less than 10 s in the primary auditory cortex, nonlinear for tasks less than 7 s in the primary motor cortex, and nonlinear for stimuli less than 3 s in the primary visual cortex. In addition, neural adaptation functions were characterized that could model the observed nonlinearities.

Acoustic Stimulation↗

Disorders of higher visual function and hemi-spatial neglect.

Lesions of the extrastriate cerebral cortex result in disorders of vision, which reveal two cortical processing streams extending ventrally and dorsally from the primary visual cortex. Current theories emphasize the visual perceptual and visuomotor specialization of the ventral and dorsal streams, respectively. Recent investigations of hemi-spatial neglect suggest that the inferior parietal region may lie at the junction of the visual and motor processing pathways.

Agnosia↗

Transient co-localization of calretinin, parvalbumin, and calbindin-D28K in developing visual cortex of monkey.

This paper reports a double-labelling immunocytochemical study of the three calcium-binding proteins calretinin, parvalbumin, and calbindin-D28k in developing and adult Macaca primary visual cortex. In adult visual cortex, each protein marks a subset of GABAergic neurons with a characteristic laminar distribution and virtually no co-localization was found between these three proteins, suggesting that each calcium-binding protein may serve as a marker for one or more cortical subcircuits. The immature visual cortex, immunostained using identical techniques was then analysed to determine if each calcium-binding protein could serve as a developmental marker for these circuits. The Cajal-Retzius cells of layer 1 contained all three proteins during development. Calbindin-D28k and calretinin were co-localized starting at Fd (foetal day) 45 and after Fd125, parvalbumin also was present in the same Cajal-Retzius cells. All three proteins continued to be expressed until the Cajal-Retzius disappeared postnatally. In layers 2-6 calbindin-D28k and calretinin were never co-localized. In contrast, parvalbumin and calretinin were found in neurons of deep layer 3 from Fd 155 to postnatal (P6) weeks with a few persisting even later. Before birth almost all PV+ neurons in layers 4-6 were CaB+, but by P3 weeks only a few PV+/CaB+ neurons remained in layer 4C and these completely disappeared by P6 weeks. Co-localization in layer 4 neurons overlaps the period of ocular dominance segregation, suggesting that the onset of cortical maturity coincides with segregation of calcium-binding proteins within the GABA interneurons.

Animals↗

Interocular suppression in the visual cortex of strabismic cats.

Strabismic humans usually experience powerful suppression of vision in the nonfixating eye. In an attempt to demonstrate physiological correlates of such suppression, we recorded from the primary visual cortex of cats with surgically induced squint and studied the responses of neurons to drifting gratings of different orientation, spatial frequency, and contrast in the two eyes. Only 1 of 50 apparently monocular cells showed any evidence of remaining, subliminal excitatory input from the "silent" eye when the two eyes were stimulated with gratings of similar orientation, and even among the small proportion of cells that remained binocularly driven, very few exhibited facilitation when stimulated binocularly. The majority of cells from both exotropes and esotropes, even those that could be independently driven through either eye, displayed nonspecific interocular suppression: stimulation of the nondominant eye with a drifting grating of any orientation depressed the response to an optimal grating being presented to the dominant eye. This phenomenon exhibited a gross nonlinearity in that it was dependent on the temporal sequence of stimulus presentation: stimulation of the nondominant eye caused significant suppression only if the neuron was already responding to an appropriate stimulus in the dominant eye, but not when onset of stimulation in the two eyes was simultaneous. Interocular suppression was always independent of the relative spatial phase of the two grating stimuli, and usually broadly tuned for the spatial frequency of the suppressive stimulus. Suppression may depend on inhibitory interaction between neighboring ocular dominance columns, combined with the loss of conventional disparity-selective binocular interactions for matched stimuli in the two eyes. The similarity of interocular suppression in strabismic cats and that caused by orthogonal gratings in the two eyes in normal cats (Sengpiel and Blakemore, 1994; Sengpiel et al., 1994) suggests that strabismic suppression and binocular rivalry depend on similar neural mechanisms.

Animals↗

State-dependent receptive-field restructuring in the visual cortex.

To extract important information from the environment on a useful timescale, the visual system must be able to adapt rapidly to constantly changing scenes. This requires dynamic control of visual resolution, possibly at the level of the responses of single neurons. Individual cells in the visual cortex respond to light stimuli on particular locations (receptive fields) on the retina, and the structure of these receptive fields can change in different contexts. Here we show experimentally that the shape of receptive fields in the primary visual cortex of anaesthetized cats undergoes significant modifications, which are correlated with the general state of the brain as assessed by electroencephalography: receptive fields are wider during synchronized states and smaller during non-synchronized states. We also show that cortical receptive fields shrink over time when stimulated with flashing light spots. Finally, by using a network model we account for the changing size of the cortical receptive fields by dynamically rescaling the levels of excitation and inhibition in the visual thalamus and cortex. The observed dynamic changes in the sizes of the cortical receptive field could be a reflection of a process that adapts the spatial resolution within the primary visual pathway to different states of excitability.

Animals↗

Orientation dependent modulation of apparent speed: a model based on the dynamics of feed-forward and horizontal connectivity in V1 cortex.

Psychophysical and physiological studies suggest that long-range horizontal connections in primary visual cortex participate in spatial integration and contour processing. Until recently, little attention has been paid to their intrinsic temporal properties. Recent physiological studies indicate, however, that the propagation of activity through long-range horizontal connections is slow, with time scales comparable to the perceptual scales involved in motion processing. Using a simple model of V1 connectivity, we explore some of the implications of this slow dynamics. The model predicts that V1 responses to a stimulus in the receptive field can be modulated by a previous stimulation, a few milliseconds to a few tens of milliseconds before, in the surround. We analyze this phenomenon and its possible consequences on speed perception, as a function of the spatio-temporal configuration of the visual inputs (relative orientation, spatial separation, temporal interval between the elements, sequence speed). We show that the dynamical interactions between feed-forward and horizontal signals in V1 can explain why the perceived speed of fast apparent motion sequences strongly depends on the orientation of their elements relative to the motion axis and can account for the range of speed for which this perceptual effect occurs (Georges, Seriès, Frégnac and Lorenceau, this issue).

Humans↗

Long-distance feedback projections to area V1: implications for multisensory integration, spatial awareness, and visual consciousness.

It is generally agreed that information flow through the cortex is constrained by a hierarchical architecture. Recent experimental evidence suggests that projections descending the hierarchy and targeting the primary visual cortex (area V1) may play an essential role in perceptual processes. We have, therefore, reexamined feedback projections to area V1, using retrograde tracer injections in this area In addition to well-known areas, quantification of labeling in higher cortical areas reveals a number of hitherto unknown long-distance feedback connections originating from auditory (A1), multisensory (STP) cortices, but also from a perirhinal area (36). These feedback projections from advanced cortical stations, a global feature shared by areas that belong to the ventral visual stream, could play an important role in early multisensory integration and spatial awareness and could provide the physical substrate for the involvement of area V1 in visual consciousness.

Auditory Cortex↗

NMDA receptor-dependent oscillatory signal outputs from the retrosplenial cortex triggered by a non-NMDA receptor-dependent signal input from the visual cortex.

The retrosplenial cortex is located at a critical juncture between the visual cortex and hippocampal formation. Functions of the retrosplenial cortex at the local circuit level, however, remain unclear. Herein, we show how signals traveling from the visual cortex behave in local circuits of the retrosplenial cortex, using optical recording methods and application of caffeine to rat brain slices. Electrical signals evoked in the primary visual cortex penetrated into the deep layer of the retrosplenial granular a cortex (RSGa) and propagated further toward postsubiculum and upper layer. Non-N-methyl-D-aspartate (NMDA) receptor-dependent initial traveling signal from the visual cortex triggered NMDA receptor-dependent neural oscillation in the RSGa. Oscillatory signals originated from the local area in the deep layer of the RSGa, and the signal spread back and forth toward the visual cortex and postsubiculum, in addition to spreading toward the upper layer. From the perspective of the RSGa, extrinsic signal inputs from the visual cortex switched on neural oscillators in the RSGa that deliver NMDA receptor-dependent intrinsic signal outputs. Opening and strengthening of non-NMDA receptor-dependent input pathways from the visual cortex required NMDA receptor-dependent oscillatory neural activities. These input and output relationships indicate that the retrosplenial cortex may represent an important relay station between the visual cortex and hippocampal formation.

Animals↗

Differential depression of inhibitory synaptic responses in feedforward and feedback circuits between different areas of mouse visual cortex.

Recordings of synaptic responses of pyramidal neurons to feedback (FB) inputs from higher to lower areas of visual cortex show that excitatory synaptic responses are only weakly opposed by disynaptic inhibition. Whether weak inhibition is preserved at high frequencies remains unknown. Whole-cell recordings were performed in pyramidal cells of mouse visual cortex to study the frequency dependence of excitatory and inhibitory postsynaptic currents (EPSCs, IPSCs) elicited by feedforward (FF) input from the primary visual cortex (V1) to the higher lateromedial area (LM) and by FB input from the LM to V1. EPSCs showed similar frequency dependencies in FF and FB pathways; the amplitudes decreased during stimulus trains, and the depression was larger at higher frequencies. IPSCs decreased during repetitive stimulation, and the depression increased at higher frequencies. At >20 Hz, the depression of IPSCs in the FB pathway was greater than in the FF pathway. Thus, unlike FF circuits, FB circuits provide balanced excitatory and inhibitory inputs across a wide range of frequencies. This property was shown to be critically important in cortical circuits that modulate the gain of pyramidal cell firing (Chance et al. [2002] Neuron 35:773-782).

6-Cyano-7-nitroquinoxaline-2,3-dione↗