Alberto De Capua

Effects of repetitive transcranial magnetic stimulation on chronic tinnitus: a randomised, crossover, double blind, placebo controlled study

Background: Chronic tinnitus is a disabling, almost untreatable, condition, usually accompanied by psychiatric distress. In patients with complex neuropsychiatric diseases, such as chronic pain, with which tinnitus shares pathophysiological similarities, placebo effects may be pronounced. Moreover, it may be difficult to distinguish actual repetitive transcranial magnetic stimulation (rTMS) induced clinical benefits beyond placebo effects in neuropsychiatric patients. Methods: 16 patients with chronic tinnitus underwent a randomised, double blind, crossover, placebo controlled trial of 1 Hz rTMS (120% of motor threshold; 1200 stimuli/day for 5 days) of the left temporoparietal region. Patients were screened for psychiatric comorbidity; additionally, anxiety and depression were monitored throughout the study. Moreover, an original placebo rTMS procedure produced the same activation of ipsilateral face muscles (a condition which may per se change the subjective rating of tinnitus) as the real rTMS. Results: There were 8 out of 14 responders. Two patients dropped out for transient worsening of tinnitus. Active rTMS induced an overall significant, but transient, improvement (35% of the basal score) of subjective tinnitus perception that was independent of either tinnitus laterality or mood or anxiety changes. No correlations were found between response to rTMS and tinnitus duration, initial subjective score or patient age. When asked after the study was over, 71.4% of patients failed to identify the temporal sequence of the real or sham rTMS interventions. Conclusion: The beneficial effects of rTMS on tinnitus are independent of mood changes. Moreover, they appear in the context of an original placebo stimulation designed to more closely replicate the somatic sensation of active stimulation. Because of the limited temporal duration of the clinical benefit, these neuromodulatory effects could be mediated by transient functional changes taking place in the neural circuits underlying tinnitus processing.

Dysfunctions of Cortical Excitability in Drug-Naïve Posttraumatic Stress Disorder Patients

BACKGROUND The investigation of a wide set of transcranial magnetic stimulation (TMS)-related variables in both hemispheres might help to identify a pattern of cortical excitability changes in posttraumatic stress disorder (PTSD) patients, reflecting gamma-amino-butiric acid (GABA)/glutamate balance and dysfunction, and to determine whether some of these variables are related to clinical features. METHODS In 20 drug-naive PTSD patients without comorbidity and 16 matched healthy control subjects we tested bilaterally with standard TMS procedures: resting motor threshold (RMT) to single-pulse TMS (reflecting ion channel function), paired-pulse short-latency intracortical inhibition (SICI; mainly reflecting GABA(A) function) and intracortical facilitation (ICF; mainly reflecting glutamatergic function), single-pulse cortical silent period (CSP; mainly reflecting GABA(B)-ergic function), and paired-pulse short-latency afferent inhibition (SAI; reflecting cholinergic mechanisms and their presynaptic GABA(A)-mediated modulation). RESULTS The PTSD patients showed widespread impairment of GABA(A)-ergic SICI, which was reversed toward facilitation in both hemispheres in one-half of the patients, marked increase of glutamatergic ICF in the right hemisphere, and right-sided impairment of SAI. Illness duration and avoidance symptoms but not anxiety correlated with right-lateralized dysfunctions of cortical excitability. CONCLUSIONS Although the neurobiological complexity of each TMS variable makes current results theoretical, the pattern of cortical excitability accompanying PTSD symptoms suggests a bilateral decrease of the GABA(A)-ergic function. This prevails in the right hemisphere, in association with a relative prevalence of the glutamatergic tone, a new finding that current neuroimaging investigations cannot provide due to the lack of reliable glutamate tracers. Results might help to disclose new pathophysiological aspects of PTSD symptoms, providing a rationale for future neuromodulatory strategies of treatment.

Distinct Olfactory Cross-Modal Effects on the Human Motor System

Background Converging evidence indicates that action observation and action-related sounds activate cross-modally the human motor system. Since olfaction, the most ancestral sense, may have behavioural consequences on human activities, we causally investigated by transcranial magnetic stimulation (TMS) whether food odour could additionally facilitate the human motor system during the observation of grasping objects with alimentary valence, and the degree of specificity of these effects. Methodology/Principal Findings In a repeated-measure block design, carried out on 24 healthy individuals participating to three different experiments, we show that sniffing alimentary odorants immediately increases the motor potentials evoked in hand muscles by TMS of the motor cortex. This effect was odorant-specific and was absent when subjects were presented with odorants including a potentially noxious trigeminal component. The smell-induced corticospinal facilitation of hand muscles during observation of grasping was an additive effect which superimposed to that induced by the mere observation of grasping actions for food or non-food objects. The odour-induced motor facilitation took place only in case of congruence between the sniffed odour and the observed grasped food, and specifically involved the muscle acting as prime mover for hand/fingers shaping in the observed action. Conclusions/Significance Complex olfactory cross-modal effects on the human corticospinal system are physiologically demonstrable. They are odorant-specific and, depending on the experimental context, muscle- and action-specific as well. This finding implies potential new diagnostic and rehabilitative applications.

Modulation of high-frequency (600 Hz) somatosensory-evoked potentials after rTMS of the primary sensory cortex.

Somatosensory inputs to the primary sensory cortex (S1) after median nerve stimulation include temporally overlapping parallel processing, as reflected by standard low‐frequency somatosensory‐evoked potentials (LF‐SEPs) and high‐frequency SEPs (HF‐SEPs), the latter being more sensitive to arousal and to other rapid adaptive changes. Experimental data suggest that cortical HF‐SEPs are formed by two successive pre‐ and postsynaptic components, respectively, generated in the terminal part of thalamo‐cortical radiation (early burst) and in specialized neuronal pools within S1 (later burst).

Temporal Dynamics of Memory Trace Formation in the Human Prefrontal Cortex

Event-related repetitive transcranial magnetic stimulation (rTMS) can dynamically interfere with the memory encoding of complex visual scenes. Here, we investigated the critical time elapsing from stimulus presentation to the formation of an effective memory trace by delivering rTMS (900 ms at 20 Hz) during the encoding of visual scenes at different poststimulus delays (from 100 to 500 ms) in 28 healthy volunteers. The stimulation delay showed a robust inverse correlation with the correct retrieval of encoded images. In particular, rTMS stimulation delivered with a delay of 500 ms and lasting for 400 ms after stimulus offset resulted in a huge drop in retrieval accuracy. Such a timing suggests that rTMS affects the formation of long-term memory through interference with postperceptual executive processes, rather than with perceptual analysis of the stimuli. The effect was specific for stimulation of the left dorsolateral prefrontal cortex (DLPFC), whereas rTMS applied to the right DLPFC, vertex (active control site), as well as sham stimulation (placebo) did not affect accuracy. These results confirm the crucial role of the left DLPFC in encoding and provide novel information about the critical timing of its engagement in the formation, consolidation, and maintenance of the memory trace.

rTMS for PTSD: Induced merciful oblivion or elimination of abnormal hypermnesia?

Neuroimaging studies and experimental data suggest that symptoms of posttraumatic stress disorder (PTSD) are associated with dysfunctions of neural circuits linking prefrontal cortex and the limbic system that have a role in autobiographic episodic memory. High-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) has been suggested to be beneficial to patients with PTSD, transiently alleviating re-experiencing as well as avoidance reactions and associated anxiety symptoms. In healthy humans, converging evidence suggests that rTMS of the right DLPFC interferes with episodic memory retrieval. Hence, we hypothesize that daily applications of rTMS in PTSD patients may reduce access to the set of autobiographical stored events, that, if re-experienced, may cause the overt PTSD symptoms.

Use of venlafaxine in psychiatric disorders and climacteric syndrome: is a therapeutic bridge?

Objective: To verify the efficacy of the double-action mechanism of venlafaxine for depression and climacteric symptoms. Methods: A group of 20 postmenopausal women (age range 40–60 years) with diagnosis of major depressive disorder, generalized anxiety disorder and climacteric symptoms was enrolled. All participants received venlafaxine (75 mg/day) for 2 months. Clinical checkup and evaluation test were repeated every 2 weeks for 2 months of treatment. Results: Before treatment, the mean scores for the clinical evaluation scales (Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale) were 13.9 and 18.7, respectively (mild–moderate severity). The general level of psychopathology was not particularly high (Symptomatology Checklist-90, mean total 103), the most common psychopathological dimensions were depression and somatization. The sample suffered from mild climacteric syndrome (Kupperman Index Score, mean = 19.1). Clinical improvement was visible after 2 weeks of treatment and continued until the last checkup, 2 months after the start of treatment (final Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale scores: 5.1 and 6.3, respectively). Kupperman Index Scores at the end of the treatment period demonstrated complete resolution of the climacteric syndrome (mean score = 6.57). Conclusion: Venlafaxine is efficacy in treating both psychiatric disorders and climacteric symptomatology.

P006 Cross-modal olfactory effects on human motor system as revealed by transcranial magnetic stimulation

to a random sequence in 7th block, indicated that participants learned the regularities of the sequence they were presented within the SRT. Grand averaged ERPs showed that a larger positive potential (P2) appeared around 200 ms after stimuli onset over the fronto-medial and central areas. The P2 component showed larger amplitudes with more learning, and were highly correlated with RT (r = 0.93). To reveal the source of this learning-related potential we did a current density analysis for each learning block using LORETA and found that a high density source was located in the anterior cingulate cortex (ACC) (Talairach coordinates, x, y, z: 4, 10, 43) in more learning blocks, but in the occipital lobe during the random block (x, y, z: 46, -74, 8). These results indicated that ERP component reflects sequence learning and continuous change in knowledge, and that the ACC is essential neural substrate for the implicit sequence learning.

TUO25 Modulation of high-frequency (600 Hz) somatosensory evoked potentials after rTMS of the primary sensory cortex

Somatosensory inputs to the primary sensory cortex (S1) after median nerve stimulation include temporally overlapping parallel processing, as reflected by standard low-frequency somatosensory-evoked potentials (LF-SEPs) and high-frequency SEPs (HF-SEPs), the latter being more sensitive to arousal and to other rapid adaptive changes. Experimental data suggest that cortical HF-SEPs are formed by two successive pre- and postsynaptic components, respectively, generated in the terminal part of thalamo-cortical radiation (early burst) and in specialized neuronal pools within S1 (later burst). In eight healthy subjects, slow (1 Hz) or rapid (10 Hz) repetitive transcranial magnetic stimulations (rTMS), which are known to induce opposite changes on cortical excitability, applied on S1 did not modify LF-SEPs, while HF-SEPs showed a series of dissociate changes in the early and later high-frequency burst, moreover occurring with a different time-course. Slow rTMS caused an immediate and lasting decrease of the later burst activity, coupled with an immediate increase of the earlier part of the burst, suggesting that inhibition of cortical excitability triggered opposite, compensatory effects at subcortical levels; rapid rTMS induced a delayed increase of later HF-SEPs, leaving unaltered the earlier subcortical burst. Findings causally demonstrate that LF- and HF-SEPs reflect two distinct functional pathways for somatosensory input processing, and that early and late high-frequency burst do actually reflect the activity of different generators, as suggested by experimental data. Possible underlying neurophysiological phenomena are discussed.