Visual response augmentation in cat (and macaque) LGN: potentiation by corticofugally mediated gain control in the temporal domain

[Abstract] Visual responses of neurons are dependent on the context of a stimulus, not only in spatial terms but also temporally, although evidence for temporally separate visual influences is meagre, based mainly on studies in the higher cortex. Here we demonstrate temporally induced elevation of visual responsiveness in cells in the lateral geniculate nucleus (LGN) of cat and monkey following a period of high intensity (elevated contrast) stimulation. This augmentation is seen in 40–70% (monkey–cat) of cells tested and of all subtypes. Peaking at ∼ 3 min following the period of intense stimulation, it can last for 10–12 min and can be repeated and summed in time. Furthermore, it is dependent on corticofugal input, is seen even when high contrast stimuli of orthogonal orientation are used and therefore results from a/any prior increase in activity in the retino-geniculo-striate pathway. We suggest that this reflects a general mechanism for control of visual responsiveness; both a flexible and dynamic means of changing effectiveness of thalamic activity as visual input changes, but also a mechanism which is an emergent property of the thalamo-cortico-thalamic loop.Xunta de Galicia; XUGA13401B96Ministerio de Educación y Cultura; FIS-97/040

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

[Abstract] We evaluated the effect of low-frequency rTMS on motor signs in Parkinson’s disease (PD), under a doubleblind placebo-controlled trial design. PD patients were randomly assigned to received either real (n 5 9) or sham (n 5 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 CVstride-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.Galicia. Consellería de Educación; 2007/000140-0Galicia. Consellería de Innovación, Industria e Comercio; PGIDIT06PXIC137004PNGalicia. Consellería de Economía e Industria; INCITE09137 379 PRMinisterio de Ciencia e Innovación; BFU2009-0816

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

[Abstract] 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 10 days 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 10 days, (100 pulses at 1 Hz) 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.Galicia. Consellería de Educación; 2007/000140-0Galicia. Consellería de Innovación, Industria e Comercio; PGIDIT06PXIC137004P

Endocannabinoid CB1 receptors modulate visual output from the thalamus

[Abstract] 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-tonoise 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.Ministerio de Ciencia e Innovación; BFU2009-08169Xunta de Galicia; 2007/000140-

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

[Abstract] 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

Changes in Visual Responses in the Feline dLGN: Selective Thalamic Suppression Induced by Transcranial Magnetic Stimulation of V1

[Abstract] 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.Ministerio de Ciencia y Tecnología; BFI2002-320

Effects on EEG of low (1Hz) and high (15Hz) frequency repetitive transcranial magnetic stimulation of the visual cortex: a study in the anesthetized cat

[Abstract] Here we confirm our earlier findings that showed 1Hz rTMS over the primary visual cortex of the anesthetized cat, known to cause inhibition of the cortex, induces an increase in power in the slow, delta band of the EEG. We also demonstrate that these inhibitory effects of 1Hz rTMS may be measured as changes of spatiotemporal receptive field parameters at the single cell level. We extend these observations to show that higher frequency stimulation of the cortex at 15Hz has the opposite effect of decreasing delta activity, which was also accompanied by significant increases in theta, alpha and beta bands. This highly reproducible EEG change may be useful as a simple marker to predict inhibitory or excitatory rTMS effects known to be dependent upon stimulation frequency.Ministerio de Educación, Cultura y Deporte; BFU2005-00502Xunta de Galicia; PGIDIT06PXIB137036P

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

[Abstract] 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.Galicia. Consellería de Educación; 2007/000140-

Central fatigue induced by short-lasting finger tapping and isometric tasks: a study of silent periods evoked at spinal and supraspinal levels

[Abstract] The neural substrates of fatigue induced by muscular activity have been addressed in depth in relation to isometric tasks. For these activities, when fatigue develops, it has been noted that the duration of the silent periods (SPs) increases in response to both transcranial magnetic stimulation (TMS) of primary motor cortex or electric cervicomedullary stimulation (CMS). However, fatigue is known to be task-dependent and the mechanisms giving rise to a decrease in motor performance during brief, fast repetitive tasks have been less studied. We hypothesized that fatigue induced by repetitive fast finger tapping may have physiological mechanisms different from those accounting for fatigue during an isometric contraction, even in cases of matched effort durations. In these tasks, we examined the contribution of spinal and supraspinal motor circuits to the production of fatigue. The tapping rate and maximal voluntary contractions (MVC), and TMS- and CMS-evoked SPs were obtained at the time of fatigue, and while subjects maintained maximal muscle activation after fast finger-tapping (or isometric activity) of different durations (10 or 30 s). Results showed different mechanisms of fatigue triggered by isometric contraction and repetitive movements, even of short duration. Short-lasting repetitive movements induce fatigue within intracortical inhibitory circuits. They increased TMS-SPs, but not CMS-SPs. On the other hand, isometric contraction had a clear impact on spinal circuits. The consideration of these differences might help to optimize the study of fatigue in physiological conditions and neurological disorders.Galicia. Consellería de Educación; 2007/000140-

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

[Abstract] 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