Melanopsin supports irradiance-driven changes in maintained activity in the superior colliculus of the mouse.

Melanopsin phototransduction allows intrinsically photosensitive retinal ganglion cells (ipRGCs) to maintain firing under sustained illumination and to encode irradiance. ipRGCs project to different parts of the visual system, including the superficial superior colliculus (sSC), but to date there is no description of melanopsin contributions to the activity of that nucleus. We sought to fill that gap using extracellular recordings to describe light response in the sSC. We failed to observe light responses in the sSC of mice lacking rod and cone function, in which melanopsin provides the only photoreception. Nor did the sSC of intact animals track very gradual ramps in irradiance, a stimulus encoded by melanopsin for other brain regions. However, in visually intact mice we did find maintained responses to extended light steps (30 s) and to an irradiance ramp upon which a high frequency (20 Hz) temporal white noise was superimposed. Both of these responses were deficient when the spectral composition of the stimulus was changed to selectively reduce its effective irradiance for melanopsin. Such maintained activity was also impaired in mice lacking melanopsin, and this effect was specific, as responses of this genotype to higher spatiotemporal frequency stimuli were normal. We conclude that ipRGCs contribute to irradiance-dependent modulations in maintained activity in the sSC, but that this effect is less robust than for other brain regions receiving ipRGC input.

The effects of expectancy on corticospinal excitability: passively preparing to observe a movement.

The corticospinal tract excitability is modulated when preparing movements. Earlier to movement execution, the excitability of the spinal cord increases waiting for supraspinal commands to release the movement. Movement execution and movement observation share processes within the motor system, although movement observation research has focused on processes later to movement onset. We used single and paired pulse transcranial magnetic stimulation on M1 (n = 12), and electrical cervicomedullary stimulation (n = 7), to understand the modulation of the corticospinal system during the "preparation" to observe a third person's movement. Subjects passively observed a hand that would remain still or make an index finger extension. The observer's corticospinal excitability rose when "expecting to see a movement" vs. when "expecting to see a still hand." The modulation took origin at a spinal level and not at the corticocortical networks explored. We conclude that expectancy of seeing movements increases the excitability of the spinal cord.

Differential feedback modulation of center and surround mechanisms in parvocellular cells in the visual thalamus.

Many cells in both the central visual system and other sensory systems exhibit a center surround organization in their receptive field, where the response to a centrally placed stimulus is modified when a surrounding area is also stimulated. This can follow from laterally directed connections in the local circuit at the level of the cell in question but could also involve more complex interactions. In the lateral geniculate nucleus (LGN), the cells relaying the retinal input display a concentric, center surround organization that in part follows from the similar organization characterizing the retinal cells providing their input. However, local thalamic inhibitory interneurons also play a role, and as we examine here, feedback from the visual cortex too. Here, we show in the primate (macaque) that spatially organized cortical feedback provides a clear and differential influence serving to enhance both responses to stimulation within the center of the receptive field and the ability of the nonclassical surround mechanism to attenuate this. In short, both center and surround mechanisms are influenced by the feedback. This dynamically sharpens the spatial focus of the receptive field and introduces nonlinearities from the cortical mechanism into the LGN.

Controlled trial on the effect of 10 days low-frequency repetitive transcranial magnetic stimulation (rTMS) on motor signs in Parkinson's disease.

We evaluated the effect of low-frequency rTMS on motor signs in Parkinson's disease (PD), under a double-blind placebo-controlled trial design. PD patients were randomly assigned to received either real (n = 9) or sham (n = 9) rTMS for 10 days. Each session comprises two trains of 50 stimuli each delivered at 1 Hz and at 90% of daily rest motor threshold using a large circular coil over the vertex. The effect of the stimulation, delivered during the ON-period, was evaluated during both ON and OFF periods. Tests were carried out before and after the stimulation period, and again 1 week after. The effect of the stimulation was evaluated through several gait variables (cadence, step amplitude, velocity, the CV(stride-time), and the turn time), hand dexterity, and also the total and motor sections of the UPDRS. Only the total and motor section of the UPDRS and the turn time during gait were affected by the stimulation, the effect appearing during either ON or OFF evaluation, and most importantly, equally displayed in both real and sham group. The rest of the variables were not influenced. We conclude the protocol of stimulation used, different from most protocols that apply larger amount of stimuli, but very similar to some previously reported to have excellent results, has no therapeutic value and should be abandoned. This contrasts with the positive reported effects using higher frequency and focal coils. Our work also reinforces the need for sham stimulation when evaluating the therapeutic effect of rTMS.

Bursting thalamic responses in awake monkey contribute to visual detection and are modulated by corticofugal feedback.

The lateral geniculate nucleus is the gateway for visual information en route to the visual cortex. Neural activity is characterized by the existence of two firing modes: burst and tonic. Originally associated with sleep, bursts have now been postulated to be a part of the normal visual response, structured to increase the probability of cortical activation, able to act as a "wake-up" call to the cortex. We investigated a potential role for burst in the detection of novel stimuli by recording neuronal activity in the lateral geniculate nucleus (LGN) of behaving monkeys during a visual detection task. Our results show that bursts are often the neuron's first response, and are more numerous in the response to attended target stimuli than to unattended distractor stimuli. Bursts are indicators of the task novelty, as repetition decreased bursting. Because the primary visual cortex is the major modulatory input to the LGN, we compared the results obtained in control conditions with those observed when cortical activity was reduced by TMS. This cortical deactivation reduced visual response related bursting by 90%. These results highlight a novel role for the thalamus, able to code higher order image attributes as important as novelty early in the thalamo-cortical conversation.

Balancing the excitability of M1 circuitry during movement observation without overt replication.

Although observation of a movement increases the excitability of the motor system of the observer, it does not induce a motor replica. What is the mechanism for replica suppression? We performed a series of experiments, involving a total of 66 healthy humans, to explore the excitability of different M1 circuits and the spinal cord during observation of simple movements. Several strategies were used. In the first and second experimental blocks, we used several delay times from movement onset to evaluate the time-course modulation of the cortico-spinal excitability (CSE), and its potential dependency on the duration of the movement observed; in order to do this single pulse transcranial magnetic stimulation (TMS) over M1 was used. In subsequent experiments, at selected delay times from movement-onset, we probed the excitability of the cortico-spinal circuits using three different approaches: (i) electric cervicomedullary stimulation (CMS), to test spinal excitability, (ii) paired-pulse TMS over M1, to evaluate the cortical inhibitory-excitatory balance (short intracortical inhibition (SICI) and intracortical facilitation (ICF)], and (iii) continuous theta-burst stimulation (cTBS), to modulate the excitability of M1 cortical circuits. We observed a stereotyped response in the modulation of CSE. At 500 ms after movement-onset the ICF was increased; although the most clear-cut effect was a decrease of CSE. The compensatory mechanism was not explained by changes in SICI, but by M1-intracortical circuits targeted by cTBS. Meanwhile, the spinal cord maintained the elevated level of excitability induced when expecting to observe movements, potentially useful to facilitate any required response to the movement observed.

Motor facilitation during real-time movement imitation in Parkinson's disease: a virtual reality study.

BACKGROUND: Impaired temporal stability and poor motor unit recruitment are key impairments in Parkinsonian motor control during a whole spectrum of rhythmic movements, from simple finger tapping to gait. Therapies based on imitation can be designed for patients with motor impairments and virtual-reality (VR) offers a new perspective. Motor actions are known to depend upon the dopaminergic system, whose involvement in imitation is unknown. We sought to understand this role and the underlying possibilities for motor rehabilitation, by observing the execution of different motor-patterns during imitation in a VR environment in subjects with and without dopaminergic deficits. METHODS: 10 OFF-dose idiopathic Parkinson's Disease patients (PD), 9 age-matched and 9 young-subjects participated. Subjects performed finger-tapping at their "comfort" and "slow-comfort" rates, while immersed in VR presenting their "avatar" in 1st person perspective. Imitation was evaluated by asking subjects to replicate finger-tapping patterns different to their natural one. The finger-pattern presented matched their comfort and comfort-slow rates, but without a pause on the table (continuously moving). RESULTS: Patients were able to adapt their finger-tapping correctly, showing that in comparison with the control groups, the dopaminergic deficiency of PD did not impair imitation. During imitation the magnitude of EMG increased and the temporal variability of movement decreased. CONCLUSIONS: PD-patients have unaltered ability to imitate instructed motor-patterns, suggesting that a fully-functional dopaminergic system is not essential for such imitation. It should be further investigated if imitation training over a period of time induces positive off-line motor adaptations with transfer to non-imitation tasks.

Endocannabinoid CB1 receptors modulate visual output from the thalamus.

RATIONALE: Endocannabinoids have emerged as a modulatory brain system affecting different types of synapses, broadly distributed throughout the CNS, which explain the diverse psychophysical effects observed following activation of the endocannabinoid system. OBJECTIVES AND METHODS: The present study aimed to characterize the effect of CB1-mediated activity in the visual thalamus. In vivo single-unit extracellular recordings were performed in anaesthetized adult pigmented rats, measuring visual and spontaneous activity, combined with application of CB1 receptor agonists (anandamide, 2-AG, and O2545) and one antagonist, AM251. RESULTS: CB1 receptors activation revealed two cellular populations, with excitatory effects on ∼28% of cells and inhibitory in ∼72%, actions which were blocked by the antagonist AM251. The agonist action significantly altered both spontaneous and visual activity, shifting the signal-to-noise ratio (S/N), with accompanying changes in the variability within the visual response. Increased responses by agonist application were accompanied by a decrease in S/N and an increase in variability, while those cells inhibited by the agonist showed an increase in S/N and a decrease in variability. There was no obvious correlation between the two effects and any other response property suggesting a more general role in modulating all information passing from LGN to cortex. CONCLUSIONS: Our data support a role for CB1 at the level of the thalamus acting as a dynamic modulator of visual information being sent to the cortex, apparently maintaining the salience of the signal within upper and lower boundaries. This may account for some of the behavioral effects of cannabis.

Assessment of 180° rotation of the choroid as a novel surgical treatment for age-related macular degeneration.

PURPOSE: Our objective was to examine the feasibility of rotating choriocapillaris, Bruch's membrane (BM), and retinal pigment epithelium (RPE) through 180° on a vascular pedicle and to assess revascularization and tissue preservation postoperatively. Such an approach could be used in the treatment of age-related macular degeneration where there is focal disease at the macula with healthy tissues located peripherally. METHODS: Successful surgery was performed in six rhesus macaque monkeys, which have a very similar choroidal blood supply to humans. After inducing a retinal detachment, the recurrent branch of the long posterior ciliary artery was used as a pedicle around which a graft stretching to the temporal equator was rotated. Retina was reattached over the rotated graft and eyes were followed up for up to 6 months with repeated angiography and optical coherence tomography (OCT). The morphology of retinal cells and BM were assessed by immunohistochemistry and electron microscopy. RESULTS: Revascularization of the choroid was limited, with reestablishment of drainage to the vortex veins seen in only one case. There was a secondary loss of the RPE and outer retina evident on histological analysis three months after surgery. The underlying BM however remained intact. CONCLUSIONS: Pedicled choroidal rotation surgery is technically feasible in vivo with intraoperative control of bleeding. However, lack of graft revascularization with the technique in its current form leads to neuroretinal and RPE tissue loss, and graft shrinkage. We found no evidence that rotational grafts are likely to improve the outcomes presently achieved with free graft techniques.

Vasomotion and neurovascular coupling in the visual thalamus in vivo.

Spontaneous contraction and relaxation of arteries (and in some instances venules) has been termed vasomotion and has been observed in an extensive variety of tissues and species. However, its functions and underlying mechanisms are still under discussion. We demonstrate that in vivo spectrophotometry, measured simultaneously with extracellular recordings at the same locations in the visual thalamus of the cat, reveals vasomotion, measured as an oscillation (0.14 hz) in the recorded oxyhemoglobin (OxyHb) signal, which appears spontaneously in the microcirculation and can last for periods of hours. During some non-oscillatory periods, maintained sensory stimulation evokes vasomotion lasting ~30s, resembling an adaptive vascular phenomenon. This oscillation in the oxyhaemoblobin signal is sensitive to pharmacological manipulation: it is inducible by chloralose anaesthesia and it can be temporarily blocked by systemic administration of adrenaline or acetylcholine (ACh). During these oscillatory periods, neurovascular coupling (i.e. the relationship between local neural activity and the rate of blood supply to that location) appears significantly altered. This raises important questions with regard to the interpretation of results from studies currently dependent upon a linear relationship between neural activity and blood flow, such as neuroimaging.

Double-blind, randomized, placebo controlled trial on the effect of 10 days low-frequency rTMS over the vertex on sleep in Parkinson's disease.

OBJECTIVE: A recent report indicates repetitive transcranial magnetic stimulation (rTMS) improves sleep in Parkinson's disease (PD). The aim of this work is to evaluate the effect of 10days rTMS on sleep parameters in PD patients. METHODS: Double-blind, placebo-controlled design. Eighteen idiopathic PD patients completed the study. Sleep parameters were evaluated through actigraphy and the Parkinson's Disease Sleep Scale (PDSS), along with depression (Hamilton Depression Rating Scale, HDS), and the Unified Parkinson's Disease Rating Scale (UPDRS). Evaluations were carried out before treatment with rTMS (pre-evaluation, PRE), after the rTMS treatment programme (post-evaluation, POST), and one week after POST (POST-2). Nine PD patients received real rTMS and the other 9 received sham rTMS daily for 10days, (100 pulses at 1Hz) applied with a large circular coil over the vertex. RESULTS: Stimulation had no effect over actigraphic variables. Conversely PDSS, HDS, and UPDRS were significantly improved by the stimulation. Notably, however, these changes were found equally in groups receiving real or sham stimulation. CONCLUSIONS: rTMS, using our protocol, has no therapeutic value on the sleep of PD patients, when compared to appropriate sham controls. Future works assessing the possible therapeutic role of rTMS on sleep in PD should control the effect of placebo.

Mixed burst and tonic firing in the thalamus: a study in the feline lateral geniculate nucleus in vivo.

Compounds known to inhibit or disfacilitate cells in cat dorsal lateral geniculate nucleus (dLGN) were applied iontophoretically in vivo. Application of GABA, or agonists of GABA(A) and GABA(B) receptors, markedly decreased responses to low frequency periodic visual stimulation, but, while causing some increases in burst firing, cells continued to produce tonic spikes even when firing was reduced to near zero. Similar actions were seen with compounds manipulating the cholinergic system. Inhibition of local Nitric Oxide production reduced firing rates but did not affect burst firing. Significant levels of tonic firing were found mixed with burst firing throughout the recordings even under conditions most favourable for bursting. We suggest that the local synaptic input to an individual dLGN cell is sufficiently dynamic to prevent the prolonged periods of burst firing which can be evoked in brain slice preparations.

Changes in visual responses in the feline dLGN: selective thalamic suppression induced by transcranial magnetic stimulation of V1.

Transcranial magnetic stimulation (TMS) of the cortex can modify activity noninvasively and produce either excitatory or inhibitory effects, depending on stimulus parameters. Here we demonstrate controlled inhibitory effects on the large corticogeniculate feedback pathway from primary visual cortex to cells of the dorsal lateral geniculate nucleus (dLGN) that are focal and reversible-induced by either single pulses or trains of pulses of TMS. These effects selectively suppress the sustained component of responses to flashed spots or moving grating stimuli and are the result of loss of spikes fired in tonic mode, whereas the number of spikes fired in bursts remain the same. We conclude that acute inactivation of the corticogeniculate downflow selectively affects the tonic mode. We found no evidence to suggest that cortical inactivation increased burst frequency.

Binocular visual responses in cells of the rat dLGN.

In the mammalian visual system the output of the retina reaches the cerebral cortex by means of a synaptic link within the thalamus, the dorsal lateral geniculate nucleus (dLGN). In higher mammals this structure is visibly laminated, such that input from the two eyes remains segregated, binocular responses in essence being seen first in the cerebral cortex. In the rat this segregation is less obvious. With only around 3-10% of retinal ganglion cells projecting axons to the ipsilateral dLGN, the dLGN may be considered basically monocular; however, these ipsilaterally projecting axons contact cells in a region described as the 'hidden lamina', whose physiological properties have not been well described. In the anatomical literature, there is some debate as to the possibility of cross-over between the terminations of the two eyes. Here, a population of cells physiologically receiving input from the ipsilateral eye is described--surprisingly, the majority (63%) had powerful, excitatory input from both eyes, suggesting a simple form of binocular integration at a stage earlier than previously described for other, more 'visually developed' species, in which thalamic binocular integration is complex.

Receptive field structure of burst and tonic firing in feline lateral geniculate nucleus.

There are two recognised modes of firing activity in thalamic cells, burst and tonic. A low-threshold (LT) burst (referred to from now on as 'burst') comprises a small number of high-frequency action potentials riding the peak of a LT Ca(2+) spike which is preceded by a silent hyperpolarised state > 50 ms. This is traditionally viewed as a sleep-like phenomenon, with a shift to tonic mode at wake-up. However, bursts have also been seen in the wake state and may be a significant feature for full activation of recipient cortical cells. Here we show that for visual stimulation of anaesthetised cats, burst firing is restricted to a reduced area within the receptive field centre of lateral geniculate nucleus cells. Consistently, the receptive field size of all the recorded neurons decreased in size proportionally to the percentage of spikes in bursts versus tonic spikes, an effect that is further demonstrated with pharmacological manipulation. The role of this shrinkage may be distinct from that also seen in sleep-like states and we suggest that this is a mechanism that trades spatial resolution for security of information transfer.