Altered motor cortex excitability in tinnitus patients: a hint at crossmodal plasticity

Idiopathic tinnitus is a frequent and often debilitating auditory phantom perception of largely unknown pathological conditions. In electrophysiological and functional neuroimaging studies, affected subjects have shown excessive spontaneous activity in the central auditory system. To further investigate the underlying central nervous component, we assessed motor cortex excitability in 19 patients with chronic tinnitus by means of transcranial magnetic stimulation (TMS). When results were compared with data from 19 healthy controls matched for age and sex, we found significantly enhanced intracortical facilitation in tinnitus patients. These findings parallel excitability changes after limb amputation and experimental deafferentation. Our results give further support to crossmodal interactions involving neuroplastic changes in some forms of tinnitus and may help to better understand mechanisms of maladaptive cortical reorganisation involved in phantom perceptions.     

Wide-field conditioning effects on small-field neurons in the posterior sigmoid gyrus of domestic cats

Single neurons were isolated in four different recording sites in sensorimotor cortex of the domestic cat, all sites being topographically related to the contralateral forepaw. Conditioning-testing interactions were made on 409 small-field neurons, the testing input being the contralateral forepaw (also the ipsilateral forepaw in the case of bilateral-field neurons) and the conditioning input being any paw that was ineffective in exciting the neuron. About 29% of the neurons showed inhibitory interactions and 23% showed facilitatory interactions. Of these, about 5.5% showed both effects, according to the conditioning site. Nearly 54% of the neurons failed to show any interaction effects. Most of the latter were isolated in the two posterior recording sites, located in somatosensory area I; the interaction effects were found predominantly in the two anterior recording sites, located in agranular tissue. Neurons that responded only to contralateral forepaw stimulation (sa neurons) and showed facilitatory interactions from the other three paws had response properties characteristic of neurons that respond to all four paws (m neurons). The sa neurons that showed inhibitory interactions from the other three paws did not differ significantly in response properties from those that showed no interaction effects. These findings are relevant to current criteria for the classification of sensorimotor cortex neurons and lead to remarks on the possible thalamic routes that mediate the interaction effects.     

The effects of cerebellar stimulation on the motor cortical excitability in neurological disorders: A review

The cerebellum regulates execution of skilled movements through neural connections with the primary motor cortex. A main projection from the cerebellum to the primary motor cortex is a disynaptic excitatory pathway relayed at the ventral thalamus. This dentatothalamocortical pathway receives inhibitory inputs from Purkinje cells of the cerebellar cortex. These pathways (cerebellothalamocortical pathways) have been characterized extensively using cellular approaches in animals. Advances in non-invasive transcranial activation of neural structures using electrical and magnetic stimulation have allowed us to investigate these neural connections in humans. This review summarizes various studies of the cerebellothalamocortical pathway in humans using current transcranial electrical and magnetic stimulation techniques. We studied effects on motor cortical excitability elicited by electrical or magnetic stimulation over the cerebellum by recording surface electromyographic (EMG) responses from the first dorsal interosseous (FDI) muscle. Magnetic stimuli were given with a round or figure eight coil (test stimulation) for primary motor cortical activation. For cerebellar stimulation, we gave high-voltage electrical stimuli or magnetic stimuli through a cone-shaped coil ipsilateral to the surface EMG recording (conditioning stimulation). We examined effects of interstimulus intervals (ISIs) with randomized condition-test paradigm, using a test stimulus given preceded by a conditioning stimulus by ISIs of several milliseconds. We demonstrated significant gain of EMG responses at an ISI of 3 ms (facilitatory effect) and reduced responses starting at 5 ms, which lasted 3-7 ms (inhibitory effect). We applied this method to patients with ataxia and showed that the inhibitory effect was only absent in patients with a lesion at cerebellar efferent pathways or dentatothalamocortical pathway. These results imply that this method activates the unilateral cerebellar structures. We confirmed facilitatory and inhibitory natures of cerebellothalamocortical pathways in humans. We can differentiate ataxia attributable to somewhere in the cerebello-thalamo-cortical pathways from that caused by other pathways.     

Lack of multiplicative transitivity in person trade-off responses

BACKGROUND: The person trade-off (PTO) is a technique for eliciting preferences for resource allocation across patient groups. In principle PTO responses should satisfy a requirement of multiplicative transitivity, i.e. that if people consider treatment of 1 in state A to be equivalent to treating 10 in state B, and 1 in state B to be equivalent to 10 in state C, then they should find 1 in state A equivalent to 100 in state C. Earlier studies addressing labelled diseases (specific diagnoses), have shown multiplicative intransitivity of the PTO responses. Our purpose was to test multiplicative transitivity in the case of health states described with the EuroQol instrument only and to find a possible framing effect such as the number of persons in the reference intervention. METHODS: Forty-four master degree students were asked to fill in a questionnaire addressing four chronic health states. Their task consisted in (1). ranking the states by severity, (2). valuing each of them by the means of the time trade-off, and (3). doing the PTO for all the 10 possible pairwise combinations of the four chronic states plus a fatal one. In a subsequent questionnaire the number of persons in the reference intervention in the PTO was increased from 10 to 100. Multiplicative transitivity was studied in subjects who demonstrated a willingness to trade off and consistency in ranking individual values. RESULTS: None of the 39 subjects included satisfied a minimum multiplicative transitivity requirement in PTO responses. Internal consistency was not improved when the PTO involved health states close to each other in terms of severity, nor when the prevention of death was not the reference intervention. For the 22 subjects having answered both types of questionnaire, increasing the number of persons in the reference intervention did not improve multiplicative transitivity.CONCLUSIONS: The PTO holds promise as a useful method for determining social preferences for priority setting, inasmuch as it captures distributive concerns that individual utility techniques such as the time trade-off do not address. But the lack of multiplicative transitivity in PTO responses is unsatisfactory, and ways to reduce this problem need to be explored.     

Mercury persistence in indoor environments in the Amazon region, Brazil

We evaluated the indoor atmospheric Hg contamination in gold trade shops in two Brazilian cities of the Legal Amazon area using the Spanish moss (Tillandsia usneoides, Bromeliaceae) as a sentinel species. Plants inside plastic cages were exposed to a controlled atmosphere to evaluate the rate of Hg retention over time and then distributed in several stores with different characteristics to enable a relative comparison. Hg concentrations were determined by cold vapor atomic absorption spectrophotometry. Plants exposed in active stores with good air circulation exhibited lower levels. Ex-gold trade shops that were kept closed for long periods exhibited higher values. Stores that have been restored before being transformed into new businesses exhibited lower values than nonrestored ones. Direct measurements suggest that indoor Hg air concentrations were below the threshold limit recommended by the World Health Organization to occupational exposure; nevertheless, restoring ex-gold trade shops could ensure a healthier working environment.     

Intracortical inhibition and facilitation upon awakening from different sleep stages: a transcranial magnetic stimulation study

Intracortical facilitation and inhibition, as assessed by the paired-pulse transcranial magnetic stimulation technique with a subthreshold conditioning pulse followed by a suprathreshold test pulse, was studied upon awakening from REM and slow-wave sleep (SWS). Ten normal subjects were studied for four consecutive nights. Intracortical facilitation and inhibition were assessed upon awakening from SWS and REM sleep, and during a presleep baseline. Independently of sleep stage at awakening, intracortical inhibition was found at 1-3-ms interstimulus intervals and facilitation at 7-15-ms interstimulus intervals. Motor thresholds were higher in SWS awakenings, with no differences between REM awakenings and wakefulness, while motor evoked potential amplitude to unconditioned stimuli decreased upon REM awakening as compared to the other conditions. REM sleep awakenings showed a significant increase of intracortical facilitation at 10 and 15 ms, while intracortical inhibition was not affected by sleep stage at awakening. While the dissociation between motor thresholds and motor evoked potential amplitudes could be explained by the different excitability of the corticospinal system during SWS and REM sleep, the heightened cortical facilitation upon awakening from REM sleep points to a cortical motor activation during this stage.     

Overexpression of calbindin D(28k) in dentate gyrus granule cells alters mossy fiber presynaptic function and impairs hippocampal-dependent memory

Calcium is a key signaling ion for induction of synaptic plasticity processes that are believed to influence cognition. Mechanisms regulating activity-induced increases in neuronal calcium and related synaptic modifications are not fully understood. Moreover, involvement of specific synapses in discrete aspects of spatial learning remains to be elucidated. We used herpes simplex amplicons to overexpress calbindin D(28k) (CaBP) selectively in dentate gyrus (DG) granule cells. We then examined the effects on hippocampal network activity by recording evoked synaptic responses in vivo and in vitro and analyzing hippocampal-dependent behavior. Relative to Lac-Z- and sham-infected controls, CaBP overexpression increased mossy fiber (MF-CA3) excitatory postsynaptic potentials and reduced paired-pulse facilitation (PPF), suggesting an increase in presynaptic strength. Additionally, CaBP overexpression reduced long-term potentiation (LTP), caused a frequency-dependent inhibition of post-tetanic potentiation (PTP), and impaired spatial navigation. Thus, increasing CaBP levels selectively in the DG disrupts MF-CA3 presynaptic function and impairs spatial cognition. The results demonstrate the power of gene delivery in the study of the neural substrates of learning and memory and suggest that mossy fiber synaptic plasticity is critical for long-term spatial memory.     

The effect of trigeminal nociceptive stimulation on blink reflexes and pain evoked by stimulation of the supraorbital nerve

The aim of this study was to investigate the effect of painful conditioning stimuli on pain and blink reflexes to supraorbital nerve stimulation. Electromyograph activity was recorded bilaterally from the orbicularis oculi muscles in 13 normal participants in response to low (2.3 mA) and high-intensity (18.6 mA) electrical stimulation of the left supraorbital nerve before, during and after the application of ice to the left or right temple or immersion of the left hand in ice-water for 60 s. The pain evoked by the high-intensity electrical stimulus was greater during painful conditioning stimulation of the ipsilateral temple than during the recovery period afterwards, and was greater than during painful conditioning stimulation of the contralateral temple. These findings imply that spatial summation of nociceptive signals across different divisions of the trigeminal nerve can heighten pain. However, painful conditioning stimulation, particularly to the right temple, strongly suppressed the R2 component of the blink reflex to the low-intensity stimulus, and also suppressed R2 to the high-intensity stimulus. Thus, an inhibitory influence (e.g. diffuse noxious inhibitory controls) appeared to mask ipsilateral segmental facilitation of R2 during ice-induced headache. This finding contrasts with recent electrophysiological evidence of trigeminal sensitization in migraine.     

Physiological evidence for a possible projection from dorsal subiculum to hippocampal area CA1

The substantial forward projection from hippocampal area CA1 to the subiculum has been comprehensively described, both anatomically and neurophysiologically. There are few data, however, regarding the existence of a backward projection from the subiculum to area CA1. We present here new electrophysiological evidence for the existence of this projection. We demonstrate a positive-going deflection in the evoked synaptic response in area CA1 following stimulation in dorsal subiculum. We also found a small, but significant, paired-pulse facilitatory effect at a 100-ms interstimulus interval. We were unable to induce long-term potentiation following high-frequency stimulation, but were able to induce short-term potentiation.     

Effect of Colonic Lactulose Availability on the Timing of Drug Release Onset in Vivo from a Unique Colon-Specific Drug Delivery System (CODES™)

Purpose. To test the hypothesis that the onset of drug release in vivo from a unique colon-specific drug delivery system (CODES) would depend on the colonic availability rate of lactulose. The site specificity of drug release in canine GI tract was also estimated. Methods. CODES tablets were prepared by tableting the granulation of acetaminophen and lactulose, followed with film coating. The pharmacokinetic performance of different CODES formulations was evaluated in six beagle dogs under fasted conditions. The release of acetaminophen and lactulose was also characterized in vitro. Results. The onset of acetaminophen release in beagle dogs was found to be dependent on the coating level of Eudragit E and lactulose loading in the core tablet. At Eudragit E coating levels of 4%, 8%, and 12% (coating weight gain), the onset of in vivo drug release occurred 5.5 (±1.9) h, 4.8 (±1.0) h. and 7.5 (±1.0) h, respectively, after dosing. A similar trend was observed when the loading of lactulose in the core tablet decreased from 78% to 58% and 38%. However, the rate and extent of acetaminophen absorption did not vary significantly in each situation based on the values of AUC and C_max. Conclusions. The onset of drug release in vivo from CODES tablets is predominantly dependent on colonic availability rate of lactulose because drug release from this system is triggered by localized drop of colonic pH from the fermentation of lactulose.