Unique Features of Subcortical Circuits in a Macaque Model of Congenital Blindness.

There is an extensive modification of the functional organization of the brain in the congenital blind human, although there is little understanding of the structural underpinnings of these changes. The visual system of macaque has been extensively characterized both anatomically and functionally. We have taken advantage of this to examine the influence of congenital blindness in a macaque model of developmental anophthalmia. Developmental anophthalmia in macaque effectively removes the normal influence of the thalamus on cortical development leading to an induced "hybrid cortex (HC)" combining features of primary visual and extrastriate cortex. Here we show that retrograde tracers injected in early visual areas, including HC, reveal a drastic reduction of cortical projections of the reduced lateral geniculate nucleus. In addition, there is an important expansion of projections from the pulvinar complex to the HC, compared to the controls. These findings show that the functional consequences of congenital blindness need to be considered in terms of both modifications of the interareal cortical network and the ascending visual pathways.

Altered Structural Connectivity of the Left Visual Thalamus in Developmental Dyslexia.

Developmental dyslexia is a highly prevalent reading disorder affecting about 5%-10% of children [1]. It is characterized by slow and/or inaccurate word recognition skills as well as by poor spelling and decoding abilities [2]. Partly due to technical challenges with investigating subcortical sensory structures, current research on dyslexia in humans by and large focuses on the cerebral cortex [3-7]. These studies found that dyslexia is typically associated with functional and structural alterations of a distributed left-hemispheric cerebral cortex network (e.g., [8, 9]). However, findings from animal models and post mortem studies in humans suggest that dyslexia might also be associated with structural alterations in subcortical sensory pathways [10-14] (reviewed in [7]). Whether these alterations also exist in dyslexia in vivo and how they relate to dyslexia symptoms is currently unknown. Here, we used ultra-high-resolution structural magnetic resonance imaging (MRI), diffusion MRI, and probabilistic tractography to investigate the structural connections of the visual sensory pathway in dyslexia in vivo. We discovered that individuals with dyslexia have reduced structural connections in the direct pathway between the left visual thalamus (lateral geniculate nucleus [LGN]) and left middle temporal area V5/MT, but not between the left LGN and left primary visual cortex. In addition, left V5/MT-LGN connectivity strength correlated with rapid naming abilities-a key deficit in dyslexia [15]. These findings provide the first evidence of specific structural alterations in the connections between the sensory thalamus and cortex in developmental dyslexia. The results challenge current standard models and provide novel evidence for the importance of cortico-thalamic interactions in explaining dyslexia.

Auditory processing and morphological anomalies in medial geniculate nucleus of Cntnap2 mutant mice.

Genetic epidemiological studies support a role for CNTNAP2 in developmental language disorders such as autism spectrum disorder, specific language impairment, and dyslexia. Atypical language development and function represent a core symptom of autism spectrum disorder (ASD), with evidence suggesting that aberrant auditory processing-including impaired spectrotemporal processing and enhanced pitch perception-may both contribute to an anomalous language phenotype. Investigation of gene-brain-behavior relationships in social and repetitive ASD symptomatology have benefited from experimentation on the Cntnap2 knockout (KO) mouse. However, auditory-processing behavior and effects on neural structures within the central auditory pathway have not been assessed in this model. Thus, this study examined whether auditory-processing abnormalities were associated with mutation of the Cntnap2 gene in mice. Cntnap2 KO mice were assessed on auditory-processing tasks including silent gap detection, embedded tone detection, and pitch discrimination. Cntnap2 knockout mice showed deficits in silent gap detection but a surprising superiority in pitch-related discrimination as compared with controls. Stereological analysis revealed a reduction in the number and density of neurons, as well as a shift in neuronal size distribution toward smaller neurons, in the medial geniculate nucleus of mutant mice. These findings are consistent with a central role for CNTNAP2 in the ontogeny and function of neural systems subserving auditory processing and suggest that developmental disruption of these neural systems could contribute to the atypical language phenotype seen in autism spectrum disorder.

Establishment of an experimental ferret ocular hypertension model for the analysis of central visual pathway damage.

Glaucoma optic neuropathy (GON) is a condition where pathogenic intraocular pressure (IOP) results in axonal damage following retinal ganglion cell (RGC) death, and further results in secondary damage of the lateral geniculate nucleus (LGN). Therapeutic targets for glaucoma thus focus on both the LGN and RGC. However, the temporal and spatial patterns of degeneration and the mechanism of LGN damage have not been fully elucidated. Suitable and convenient ocular hypertension (OH) animal models with binocular vision comparable to that of monkeys are strongly needed. The ferret is relatively small mammal with binocular vision like humans - here we report on its suitability for investigating LGN. We developed a new method to elevate IOP by injection of cultured conjunctival cells into the anterior chamber to obstruct aqueous outflow. Histologically, cultured conjunctival cells successfully proliferated to occlude the angle, and IOP was elevated for 13 weeks after injection. Macroscopically, the size of the eye gradually expanded. Subsequent enlargement of optic nerve head cupping and atrophic damage of LGN projected from the OH eye were clearly observed by anterograde staining with cholera toxin B. We believe the ferret may be a promising OH model to investigate secondary degeneration of central nervous system including LGN.

Auditory cortex stimulation to suppress tinnitus: mechanisms and strategies.

Brain stimulation is an important method used to modulate neural activity and suppress tinnitus. Several auditory and non-auditory brain regions have been targeted for stimulation. This paper reviews recent progress on auditory cortex (AC) stimulation to suppress tinnitus and its underlying neural mechanisms and stimulation strategies. At the same time, the author provides his opinions and hypotheses on both animal and human models. The author also proposes a medial geniculate body (MGB)-thalamic reticular nucleus (TRN)-Gating mechanism to reflect tinnitus-related neural information coming from upstream and downstream projection structures. The upstream structures include the lower auditory brainstem and midbrain structures. The downstream structures include the AC and certain limbic centers. Both upstream and downstream information is involved in a dynamic gating mechanism in the MGB together with the TRN. When abnormal gating occurs at the thalamic level, the spilled-out information interacts with the AC to generate tinnitus. The tinnitus signals at the MGB-TRN-Gating may be modulated by different forms of stimulations including brain stimulation. Each stimulation acts as a gain modulator to control the level of tinnitus signals at the MGB-TRN-Gate. This hypothesis may explain why different types of stimulation can induce tinnitus suppression. Depending on the tinnitus etiology, MGB-TRN-Gating may be different in levels and dynamics, which cause variability in tinnitus suppression induced by different gain controllers. This may explain why the induced suppression of tinnitus by one type of stimulation varies across individual patients.

Altered neuronal intrinsic properties and reduced synaptic transmission of the rat's medial geniculate body in salicylate-induced tinnitus.

Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.

Effective connectivity anomalies in human amblyopia.

We investigate the effective connectivity in the lateral geniculate nucleus and visual cortex of humans with amblyopia. Six amblyopes participated in this study. Standard retinotopic mapping stimuli were used to define the boundaries of early visual cortical areas. We obtained fMRI time series from thalamic, striate and extrastriate cortical regions for the connectivity study. Thalamo-striate and striate-extrastriate networks were constructed based on known anatomical connections and the effective connectivities of these networks were assessed by means of a nonlinear system identification method. The effective connectivity of all networks studied was reduced when driven by the amblyopic eye, suggesting contrary to the current single-cell model of localized signal reduction, that a significant part of the amblyopic deficit is due to anomalous interactions between cells in disparate brain regions. The effective connectivity loss was unrelated to the fMRI loss but correlated with the degree of amblyopia (ipsilateral LGN to V1 connection), suggesting that it may be a more relevant measure. Feedforward and feedback connectivities were similarly affected. A hemispheric dependence was found for the thalamo-striate feedforward input that was not present for the feedback connection, suggesting that the reduced function of the LGN recently found in amblyopic humans may not be solely determined by the feedback influence from the cortex. Both ventral and dorsal connectivities were reduced.

Corticocortical connections mediate primary visual cortex responses to auditory stimulation in the blind.

Blind individuals have to rely on nonvisual information to a greater extent than sighted to efficiently interact with the environment, and consequently exhibit superior skills in their spared modalities. These performance advantages are often paralleled by responses in the occipital cortex, which have been suggested to be essential for nonvisual processing in the blind. However, it is currently unclear through which pathways (i.e., thalamocortical or corticocortical connections) nonvisual information reaches the occipital cortex of the blind. Here, we used functional magnetic resonance imaging to study blind and matched sighted humans with an auditory discrimination paradigm and used dynamic causal modeling to investigate the effective connectivity underlying auditory activations in the primary visual cortex of blind volunteers. Model comparison revealed that a model connecting the medial geniculate nucleus (MGN), primary auditory cortex (A1), and primary visual cortex (V1) in a bidirectional manner outperformed all other models in both groups. Regarding inference on model parameters, we observed that basic auditory mechanisms (i.e., sensory input to MGN and connections from MGN to A1) did not differ significantly between the two groups. In contrast, we found clear evidence for stronger corticocortical connections from A1 to V1 in the blind, whereas results with regard to thalamocortical enhancement (from MGN to V1 and, in a control analysis, from the lateral geniculate nucleus to V1) were not consistent. These results suggest that plastic changes especially in corticocortical connectivity allow auditory information to evoke responses in the primary visual cortex of blind individuals.

Functional MRI of verbal self-monitoring in schizophrenia: performance and illness-specific effects.

Previous small-sample studies have shown altered frontotemporal activity in schizophrenia patients with auditory hallucinations and impaired monitoring of self-generated speech. We examined a large cohort of patients with schizophrenia (n = 63) and a representative group of healthy controls (n = 20) to disentangle performance, illness, and symptom-related effects in functional magnetic resonance imaging-detected brain abnormalities during monitoring of self- and externally generated speech in schizophrenia. Our results revealed activation of the thalamus (medial geniculate nucleus, MGN) and frontotemporal regions with accurate monitoring across all participants. Less activation of the thalamus (MGN, pulvinar) and superior-middle temporal and inferior frontal gyri occurred in poorly performing patients (1 standard deviation below controls' mean; n = 36), relative to the combined group of controls and well-performing patients. In patients, (1) greater deactivation of the ventral striatum and hypothalamus to own voice, combined with nonsignificant activation of the same regions to others' voice, associated positively with negative symptoms (blunted affect, emotional withdrawal, poor rapport, passive social avoidance) regardless of performance and (2) exaggerated activation of the right superior-middle temporal gyrus during undistorted, relative to distorted, feedback associated with both positive symptoms (hallucinations, persecution) and poor performance. A further thalamic abnormality characterized schizophrenia patients regardless of performance and symptoms. We conclude that hypoactivation of a neural network comprised of the thalamus and frontotemporal regions underlies impaired speech monitoring in schizophrenia. Positive symptoms and poor monitoring share a common activation abnormality in the right superior temporal gyrus during processing of degraded speech. Altered striatal and hypothalamic modulation to own and others' voice characterizes emotionally withdrawn and socially avoidant patients.

Chronic stress induces dendritic atrophy in the rat medial geniculate nucleus: effects on auditory conditioning.

Chronic stress induces dendritic atrophy in the inferior colliculus (IC, auditory mesencephalon) and impairs auditory avoidance conditioning. The aim of this study was to determine in Golgi preparations and in cued fear conditioning whether stress affects other auditory components, like the thalamic medial geniculate nucleus (MG) or the posterior thalamic nucleus (PO), in Sprague-Dawley rats. Chronic restraint stress produced a significant dendritic atrophy in the MG (stress: 407+/-55 microm; control: 808+/-120 microm; p<0.01) but did not affect auditory fear conditioning. The last result was in apparent contrast with the fact that stress impairs both the acquisition of auditory avoidance conditioned responses and the dendritic structure in two major nuclei of the auditory system. In order to analyze this disagreement, we investigated whether the stress-related freezing to tone occurring in the fear conditioning protocol corresponded to a conditioned or an unconditioned fear response, using changes in tone instead of light throughout conditioning trials. Chronic stress significantly enhanced visual fear conditioning in stressed animals compared to controls (stress: 58.9+/-8.42%, control: 23.31+/-8.01%; p<0.05), but this fear enhancement was related to unconditioned fear. Conversely, chronic stress did not affect the morphology of the PO (subserving both auditory and somatosensory information) or the corresponding auditory and somatosensory unconditioned responses (acoustic startle response and escape behavior). Our results suggest that the auditory conditioned stimulus can be processed in part independently of the IC and MG in the stressed animals, and sent to the amygdala via the PO inducing unconditioned fear. Comparable alterations could be produced in major depression.

Metallothionein I and II mitigate age-dependent secondary brain injury.

Both the immediate insult and delayed apoptosis contribute to functional deficits after brain injury. Secondary, delayed apoptotic death is more rapid in immature than in adult CNS neurons, suggesting the presence of age-dependent protective factors. To understand the molecular pathobiology of secondary injury in the context of brain development, we identified changes in expression of oxidative stress response genes during postnatal development and target deprivation-induced neurodegeneration. The antioxidants metallothionein I and II (MT I/II) were increased markedly in the thalamus of adult C57BL/6 mice compared to mice <15 days old. Target deprivation generates reactive oxygen species that mediate neuronal apoptosis in the central nervous system; thus the more rapid apoptosis observed in the immature brain might be due to lower levels of MT I/II. We tested this hypothesis by documenting neuronal loss after target-deprivation injury. MT I/II-deficient adult mice experienced greater thalamic neuron loss at 96 hr after cortical injury compared to that in controls (80 +/- 2% vs. 57 +/- 4%, P < 0.01), but not greater overall neuronal loss (84 +/- 4% vs. 79 +/- 3%, MT I/II-deficient vs. controls). Ten-day-old MT I/II-deficient mice, however, experienced both faster onset of secondary neuronal death (30 vs. 48 hr) and greater overall neuronal loss (88 +/- 2% vs. 69 +/- 4%, P = 0.02). MT I/II are thus inhibitors of age-dependent secondary brain injury, and the low levels of MT I/II in immature brains explains, in part, the enhanced susceptibility of the young brain to neuronal loss after injury. These findings have implications for the development of age-specific therapeutic strategies to enhance recovery after brain injury.

Simultaneous intracerebral EEG recordings of early auditory thalamic and cortical activity in human.

We describe documented simultaneous intracerebral auditory evoked potentials from the auditory cortex and medial geniculate body (MGB) of a human patient. The MGB response lasted > 300 ms, with an initial negativity at 13.5 ms (N13), two positive peaks P21 and P29, and two broader negativities N50 and N200. P21 and N50 amplitudes were strongest for lowest tone frequencies, suggesting possible MGB tonotopic organization. Thalamic peaks were strongly interlaced with cortical activities recorded in Heschl's gyri before 30 ms: N13 preceded the first cortical component by 3.5 ms, then P21 and P29 preceded and lagged, respectively, the following two cortical polarity reversals by 1.5-2 ms. This study provides new functional data on the human MGB, and supports a more complex than simply relay-like role of the thalamus in sound perception.

Injury-induced apoptosis of neurons in adult brain is mediated by p53-dependent and p53-independent pathways and requires Bax.

The mechanisms of injury-induced apoptosis of neurons within the CNS are not understood. We used a model of cortical injury in rat and mouse to induce retrograde neuronal apoptosis in thalamus. In this animal model, unilateral ablation of the occipital cortex causes unequivocal apoptosis of corticopetal projection neurons in the dorsal lateral geniculate nucleus (LGN) by 7 days postlesion. We tested the hypothesis that p53 and Bax regulate this retrograde neuronal apoptosis. We found, by using immunocytochemistry, that p53 accumulates in nuclei of neurons destined to undergo apoptosis. By immunoblotting, p53 levels increase ( approximately 150% of control) in nuclear-enriched fractions of the ipsilateral LGN by 5 days after occipital cortex ablation. p53 is functionally activated in nuclear fractions of the ipsilateral LGN at 5 days postlesion, as shown by DNA binding assay (approximately fourfold increase) and by immunodetection of phosphorylated p53. The levels of procaspase-3 increase at 4 days postlesion, and caspase-3 is activated prominently at 5 days postlesion. To identify whether neuronal apoptosis in the adult brain is dependent on p53 and Bax, cortical ablations were done on p53 and bax null mice. Neuronal apoptosis in the dorsal LGN is significantly attenuated (approximately 34%) in p53(-/-) mice. In lesioned p53(+/+) mice, Bax immunostaining is enhanced in the ipsilateral dorsal LGN and Bax immunoreactivity accumulates at perinuclear locations in dorsal LGN neurons. The enhancement and redistribution of Bax immunostaining is attenuated in lesioned p53(-/-) mice. Neuronal apoptosis in the dorsal LGN is blocked completely in bax(-/-) mice. We conclude that neuronal apoptosis in the adult thalamus after cortical injury requires Bax and is modulated by p53.

Descending auditory system/cerebellum/tinnitus.

The cerebellum and the descending auditory system (DAS) are considered clinically significant for influencing the development of the clinical course of tinnitus of the severe disabling type. It is hypothesized that the SPECT of Brain perfusion asymmetries in cerebellum, demonstrated since 1993, reflect clinically the influence of an aberrant auditory stimulus i.e. tinnitus, on the activity and function of the descending auditory system highlighted by the cerebellum and the acousticomotor systems. SPECT of Brain perfusion asymmetries in the cerebellum have been demonstrated in 60-70% of tinnitus patients of the central type. Electrophysiologic support for this finding includes interference in ocular fixation suppression of the vestibulocular (VOR) with rotation and position testing. Abnormalities in cerebellar function are considered to reflect the psychomotor component of tinnitus. Support for the hypothesis is demonstrated with one patient with a predominantly central type tinnitus of the severe disabling type with cerebellar perfusion asymmetries and associated electrophysiologic evidence of interference in the VOR with rotation testing.

Auditory evoked potentials in a patient with a unilateral lesion of the inferior colliculus and medial geniculate body.

Brain-stem, middle latency and late auditory evoked potentials (BAEPs, MLAEPs and LAEPs, respectively) were recorded in a patient 2 months after removal of affecting the quadrigeminal plate. Simultaneously, MRI showed a left unilateral lesion involving the inferior colliculus, brachium colliculi and the medial geniculate body (MGB). On dichotic listening, there was complete extinction of the right ear input, without subjective auditory disturbance. BAEPs were abnormal after stimulation of the right ear alone. Wave V was delayed and reduced in amplitude, and the I-V interval was augmented. Above all, MLAEPs of both ears were very abnormal. The Pa and Na components over the left hemisphere were abolished (Pa) or very reduced in amplitude or abolished (Na) whereas both Pa and Na components over the right hemisphere were normal. LAEPs were asymmetrical, with reduced P1N1P2 complex over the left hemisphere and absence of polarity reversal over the mastoid. It has been demonstrated that a lesion affecting only the inferior colliculus and MGB unilaterally and not extending beyond the MGB can abolish Na and Pa ipsilaterally. Any discussion of Na and Pa sources should take into account the output of the MGB to the auditory radiations, the MGB, the brachium colliculi and the inferior colliculus.

Auditory middle-latency responses in patients with localized and non-localized lesions of the central nervous system.

Auditory middle-latency responses were recorded in 45 neurological patients. In 4 patients with localized lesions in the thalamus, or subcortical white matter, the component Na was attenuated or delayed at T3, Cz and T4, exclusively on stimulation of the ear contralateral to the lesion. In 5 patients with temporal lobe lesions with receptive aphasia, the amplitude of component Pa was decreased on the lesion side (T3), regardless of the side of stimulation. These findings suggest that Na is generated from a subcortical structure and Pa is generated from the temporal cortex. In 25 patients with diffuse CNS lesions, V-Na interpeak latency was prolonged in 2 cases.

Acute effects of sodium valproate on epileptic photosensitivity in the lateral geniculate-kindled cat.

Epileptic photosensitivity was acquired as a result of kindling in the lateral geniculate body (GL), and a GL-kindled cat pretreated with DL-allylglycine was found to be a useful model of epilepsy for assessing the efficacy of anticonvulsant drugs. In the present study the acute anticonvulsant effects of sodium valproate (VPA) were examined in the GL-kindled cat under DL-allylglycine. An intravenous injection of VPA at 50 mg/kg induced a protective action against photically induced seizures and paroxysmal EEG activities. This protection persisted for up to 4 hours of the observation period and corresponded to plasma concentrations (61 to 123 micrograms/ml) similar to those considered therapeutic in humans. The present findings are consistent with those obtained in other animal models of photosensitive epilepsy, and lend experimental support to the idea that VPA possesses antiepileptic activity in human photosensitive epilepsy.

A new experimental model for drug studies: effects of phenobarbital and phenytoin on photosensitivity in the lateral geniculate-kindled cat.

Photosensitivity was acquired as a result of kindling in the lateral geniculate body (GL), and the GL-kindled cat pretreated with DL-allylglycine showed a stable level of photosensitivity. To test the usefulness as a model for the evaluation of anticonvulsant drugs, the effects of phenobarbital (PB) and phenytoin (PHT) on photosensitivity were studied in the GL-kindled cat under DL-allylglycine. PB (5 and 10 mg/kg intravenously, i.v.) completely suppressed photically induced seizures in most subjects at plasma concentrations of 7-16 micrograms/ml, and this anticonvulsant action persisted for at least 4 h after the injection. PHT (15 mg/kg, i.v.) at plasma concentrations of 9-15 micrograms/ml produced toxic signs, e.g., pupil dilatation, hypersalivation, and tachypnea. At this dose, PHT was inactive against photically induced myoclonus but prevented the elicitation of a generalized tonic-clonic convulsion. From these results showing that the effects of anticonvulsant drugs on photically induced seizures can be assessed in relation to plasma concentration and acute neurologic toxicity, we suggest that the GL-kindled cat is a potentially useful animal model of epilepsy for testing the efficacy of anticonvulsant drugs.

Nonhaemorrhagic thalamic infarction. Clinical, neuropsychological and electrophysiological findings in four anatomical groups defined by computerized tomography.

Twenty-five patients with nonhaemorrhagic infarcts of the thalamus were studied clinically and by neuropsychological testing, computerized tomography and somatosensory evoked response (SER) recordings. Our aim was to determine whether the findings in these different tests would form distinct symptom clusters associated with different anatomical territories of the thalamus. Infarction conforming to the tuberothalamic arterial territory caused a facial paresis for emotional movements, severe neuropsychological deficits and a delay of the SER after P14. Infarction conforming to the interpeduncular profundus arterial territory caused a supranuclear vertical gaze paresis, severe neuropsychological deficits and a delay in the P60 component of the SER. Infarction conforming to the anterior choroidal territory caused a hemiparesis, moderate neuropsychological deficits and varied sensory evoked responses. Patients with infarctions conforming to the entire geniculothalamic territory had sensory loss in multiple modalities, minimal neuropsychological deficits and absence of sensory evoked responses after P14. A lacune in this territory caused pure hemisensory loss involving part of the body for the modalities of pain and light touch but not proprioception or vibration. Neuropsychological deficits were uncommon and N32 and N60 were delayed in the SER.

[Effects of a cortical after-discharge on lateral geniculate neurones. Electrophysiological study in the chronic cat (author's transl)]. / Effets d'une post-decharge corticale sur les neurones du corps genouille lateral. Etude electrophysiologique chez le chat chronique.

(1) A chronic preparation is described in which it is possible to record juxtacellularly from identified thalamo-cortical relay (TCR) neurones in lateral geniculate body (LGB) of normally respiring, nonanaesthetized cats during natural sleep. (2) Cellular events were analyzed during and after focal electrical stimulation of homotopic visual cortex. (3) Projection of cortical epileptiform after-discharge (EAD) was strictly limited to functionally related areas of LGB. Of the 47 neurones tested only 30% were activated. (4) During the 2 sec, 50 c/sec tetanus the cortically evoked IPSPs in TCR cells were replaced by facilitation of cortico-thalamic transmission as demonstrated by the occurrence of a burst of action potentials (AP) following the antidromic AP. (5) During the ensuing EAD, high frequency AP discharges occurred in the cortico-thalamic axons during each cortical wave. This period was accompanied by prolonged (50-300 msec) low amplitude rhythmic depolarisations leading to temporary spike inactivation of TCR neurones. Comparable inactivating responses were recorded during paradoxical sleep. (6) Between paroxysmal bursts facilitation of synaptic transmission to the optic tract stimulation was observed. (7) Persistence of a positive collision test after a spontaneous AP indicates that AP are orthodromically propagated during the EAD.