Emanuele Lo Gerfo

Changes in intracortical circuits of the human motor cortex following theta burst stimulation of the lateral cerebellum

OBJECTIVE The cerebellum takes part in several motor functions through its influence on the motor cortex (M1). Here, we applied the theta burst stimulation (TBS) protocol, a novel form of repetitive Transcranial Magnetic Stimulation (rTMS) over the lateral cerebellum. The aim of this study was to test whether TBS of the lateral cerebellum could be able to modulate the excitability of the contralateral M1 in healthy subjects. METHODS Motor-evoked potentials (MEPs) amplitude, short intracortical inhibition (SICI), long intracortical inhibition (LICI) and short intracortical facilitation (SICF) were tested in the M1 before and after cerebellar continuous TBS (cTBS) or intermittent TBS (iTBS). RESULTS We found that cTBS induced a reduction of SICI and an increase of LICI. On the other hand, cerebellar iTBS reduced LICI. MEPs amplitude also differently vary following cerebellar stimulation with cTBS or iTBS, resulting in a decrease by the former and an increase by the latter. CONCLUSIONS Although the interpretation of these data remains highly speculative, these findings reveal that the cerebellar cortex undergoes bidirectional plastic changes that modulate different intracortical circuits within the contralateral primary motor cortex. SIGNIFICANCE Long-lasting modifications of these pathways could be useful to treat various pathological conditions characterized by an altered cortical excitability.

Representation of time intervals in the right posterior parietal cortex: Implications for a mental time line

Space and time interact with each other in the cognitive system. Recent studies indicate the posterior parietal cortex (PPC) as the neural correlate of spatial-temporal interactions. We studied whether the contribution of the PPC becomes critical in tasks requiring the performance of spatial computations on time intervals. We adopted an integrated neuropsychological and transcranial magnetic stimulation (rTMS) approach, presenting behavioural timing tasks to both healthy subjects and right-brain-damaged patients with and without evidence of spatial neglect. rTMS of the right PPC of healthy subjects induced a lateralised bias during a task requiring setting the midpoint of a time interval. This bias mimicked the rightward bias observed in tasks requiring setting the midpoint of line intervals. These effects were selectively encountered when rTMS was applied during the retrieval phase of the task, while no effects were observed during the initial encoding phase of the time interval. Similar effects were also observed during bisection of time intervals by right-brain-damaged patients with spatial neglect. The specific role of the right PPC in bisection of physical intervals was confirmed by an experiment in which line segments were used. These findings document the neural correlates of spatial-temporal interactions and argue for a linear metric representation of time intervals.

Cortical networks of procedural learning: evidence from cerebellar damage.

The lateral cerebellum plays a critical role in procedural learning that goes beyond the strict motor control functions attributed to it. Patients with cerebellar damage show marked impairment in the acquisition of procedures, as revealed by their performance on the serial reaction time task (SRTT). Here we present the case of a patient affected by ischemic damage involving the left cerebellum who showed a selective deficit in procedural learning while performing the SRTT with the left hand. The deficit recovered when the cortical excitability of an extensive network involving both cerebellar hemispheres and the dorsolateral prefrontal cortex (DLPFC) was decreased by low-frequency repetitive transcranial magnetic stimulation (rTMS). Although inhibition of the right DLPFC or a control fronto-parietal region did not modify the patients performance, inhibition of the right (unaffected) cerebellum and the left DLPFC markedly improved task performance. These findings could be explained by the modulation of a set of inhibitory and excitatory connections between the lateral cerebellum and the contralateral prefrontal area induced by rTMS. The presence of left cerebellar damage is likely associated with a reduced excitatory drive from sub-cortical left cerebellar nuclei towards the right DLPFC, causing reduced excitability of the right DLPFC and, conversely, unbalanced activation of the left DLPFC. Inhibition of the left DLPFC would reduce the unbalancing of cortical activation, thus explaining the observed selective recovery of procedural memory.

TMS activation of interhemispheric pathways between the posterior parietal cortex and the contralateral motor cortex

Using a twin coil transcranial magnetic stimulation (tc‐TMS) approach we have previously demonstrated that facilitation may be detected in the primary motor cortex (M1) following stimulation over the ipsilateral caudal intraparietal sulcus (cIPS). Here we tested the interhemispheric interactions between the IPS and the contralateral motor cortex (M1). We found that conditioning the right cIPS facilitated contralateral M1 when the conditioning stimulus had an intensity of 90% resting motor threshold (RMT) but not at 70% or 110% RMT. Facilitation was maximal when the interstimulus interval (ISI) between cIPS and M1 was 6 or 12 ms. These facilitatory effects were mediated by interactions with specific groups of interneurons in the contralateral M1. In fact, short intracortical inhibition (SICI) was reduced following cIPS stimulation. Moreover, additional comparison of facilitation of responses evoked by anterior–posterior versus posterior–anterior stimulation of M1 suggested that facilitation was more effective on early I1/I2 circuits than on I3 circuits. In contrast to these effects, stimulation of anterior IPS (aIPS) at 90% RMT induced inhibition, instead of facilitation, of contralateral M1 at ISIs of 10–12 ms. Finally, we found similar facilitation between left cIPS and right M1 although the conditioning stimuli had to have a higher intensity compared with stimulation of right cIPS (110% instead of 90% RMT). These findings demonstrate that different subregions of the posterior parietal cortex (PPC) in humans exert both facilitatory and inhibitory effects towards the contralateral primary motor cortex. These corticocortical projections could contribute to a variety of motor tasks such as bilateral manual coordination, movement planning in space and grasping.

Changes in cerebello-motor connectivity during procedural learning by actual execution and observation

The cerebellum is involved in motor learning of new procedures both during actual execution of a motor task and during observational training. These processes are thought to depend on the activity of a neural network that involves the lateral cerebellum and primary motor cortex (M1). In this study, we used a twin-coil TMS technique to investigate whether execution and observation of a visuomotor procedural learning task is related to modulation of cerebello-motor connectivity. We observed that, at rest, a magnetic conditioning pulse applied over the lateral cerebellum reduced the motor-evoked potentials obtained by stimulating the contralateral M1, indicating activation of a cerebello-motor connection. Furthermore, during procedural learning, cerebellar stimulation resulted in selective facilitation, not inhibition, of contralateral M1 excitability. The effects were evident when motor learning was obtained by actual execution of the task or by observation, but they disappeared if procedural learning had already been acquired by previous observational training. These results indicate that changes in cerebello-motor connectivity occur in relation to specific phases of procedural learning, demonstrating a complex pattern of excitatory and inhibitory drives modulated across time.

Motor and Linguistic Linking of Space and Time in the Cerebellum

Background Recent literature documented the presence of spatial-temporal interactions in the human brain. The aim of the present study was to verify whether representation of past and future is also mapped onto spatial representations and whether the cerebellum may be a neural substrate for linking space and time in the linguistic domain. We asked whether processing of the tense of a verb is influenced by the space where response takes place and by the semantics of the verb. Principal Findings Responses to past tense were facilitated in the left space while responses to future tense were facilitated in the right space. Repetitive transcranial magnetic stimulation (rTMS) of the right cerebellum selectively slowed down responses to future tense of action verbs; rTMS of both cerebellar hemispheres decreased accuracy of responses to past tense in the left space and to future tense in the right space for non-verbs, and to future tense in the right space for state verbs. Conclusions The results suggest that representation of past and future is mapped onto spatial formats and that motor action could represent the link between spatial and temporal dimensions. Right cerebellar, left motor brain networks could be part of the prospective brain, whose primary function is to use past experiences to anticipate future events. Both cerebellar hemispheres could play a role in establishing the grammatical rules for verb conjugation.

Effects of inhibitory rTMS on bladder function in Parkinson's disease patients†

Patients affected by Parkinsons disease (PD) may present with lower urinary tract (LUT) dysfunction characterized by involuntary detrusor overactivity. We evaluated possible impact of a 2‐week course of low frequency 1 Hz repetitive transcranial magnetic stimulation (rTMS) on LUT behavior in eight advanced PD patients complaining of urinary disturbances. We tested the effects of rTMS measuring urodynamic examination and the International Prostate Symptoms Score (IPSS) questionnaire, used for evaluation of subjective LUTS. rTMS was able to improve temporarily LUT behavior in PD patients, increasing bladder capacity and the first sensation of filling phase. Moreover, a reduction of IPSS score was noticed, due to an improvement on filling phase symptoms. The beneficial effects assessed with the IPSS lasted for up to 2 weeks after the end of the stimulation. rTMS seems to be an effective, noninvasive alternative treatment for PD patients with urinary disturbances.

Altered Parietal-Motor Connections in Alzheimer's Disease Patients

Alzheimers disease (AD) is characterized by altered functional cortico-cortical connectivity likely due to loss of afferent and efferent connections between different cortical areas. Here we explored parieto-frontal functional connectivity in 15 AD patients and 12 healthy control subjects by means of bifocal transcranial magnetic stimulation (TMS). Conditioning stimuli were applied over the right posterior parietal cortex (PPC) at different intensities (90% and 110% of resting motor threshold, RMT). Motor evoked potentials (MEPs) were then recorded from the ipsilateral primary motor cortex at different interstimulus intervals (ISIs) ranging between 2 and 15 ms. Results showed that in healthy subjects, a conditioning TMS pulse applied over the ipsilateral PPC at 90%, but not at 110%, of RMT intensity was able to increase the excitability of the right M1. This functional interaction peaked at ISI = 6 ms. Conversely, in AD patients the facilitatory pattern of parieto-motor connections was evident only when TMS was delivered at an intensity of 110% of RMT with a peak at ISI = 8 ms. Moreover in AD patients, treatment with cholinesterase inhibitors did not induce any significant modification in the strength of the connection. In subsequent analyses, we found that, in AD patients, the effects induced by PPC conditioning at 110% RMT correlated with neuropsychological measures of episodic memory and executive functions, implying that patients with better cognitive performance had less impaired connectivity. Our findings reveal that parieto-frontal cortico-cortical functional connectivity is altered in AD patients, providing further evidence for a disconnection-based interpretation of AD symptoms.

Visual and semantic processing of living things and artifacts: An fmri study

We carried out an fMRI study with a twofold purpose: to investigate the relationship between networks dedicated to semantic and visual processing and to address the issue of whether semantic memory is subserved by a unique network or by different subsystems, according to semantic category or feature type. To achieve our goals, we administered a word–picture matching task, with within-category foils, to 15 healthy subjects during scanning. Semantic distance between the target and the foil and semantic domain of the target–foil pairs were varied orthogonally. Our results suggest that an amodal, undifferentiated network for the semantic processing of living things and artifacts is located in the anterolateral aspects of the temporal lobes; in fact, activity in this substrate was driven by semantic distance, not by semantic category. By contrast, activity in ventral occipito-temporal cortex was driven by category, not by semantic distance. We interpret the latter finding as the effect exerted by systematic differences between living things and artifacts at the level of their structural representations and possibly of their lower-level visual features. Finally, we attempt to reconcile contrasting data in the neuropsychological and functional imaging literature on semantic substrate and category specificity.

Goal Achievement Failure Drives Corticospinal Modulation in Promotion and Prevention Contexts

When making decisions, people are typically differently sensitive to gains and losses according to the motivational context in which the choice is performed. As hypothesized by Regulatory Focus Theory (RFT), indeed, goals are supposed to change in relation to the set of possible outcomes. In particular, in a promotion context, the goal is achieving the maximal gain, whereas in a prevention context it turns into avoiding the greatest loss. We explored the neurophysiological counterpart of this phenomenon, by applying Transcranial Magnetic Stimulation (TMS) and recording the motor evoked potentials (MEPs) in participants taking part in an economic game, in which they observed actions conveying different goal attainment levels, framed in different motivational contexts. More than the actual value of the economic exchange involved in the game, what affected motor cortex excitability was the goal attainment failure, corresponding to not achieving the maximal payoff in a promotion context and not avoiding the greatest snatch in a prevention context. Therefore, the results provide support for the key predictions of RFT, identifying a neural signature for the goal attainment failure.