Interval timing disruptions in subjects with cerebellar lesions

The cerebellum has long been implicated in time perception, particularly in the subsecond range. The current set of studies examines the role of the cerebellum in suprasecond timing, using analysis of behavioral data in subjects with cerebellar lesions. Eleven cerebellar lesion subjects and 17 controls were tested on temporal estimation, reproduction and production, for times ranging from 2 to 12 s. Cerebellar patients overproduced times on both the reproduction and production tasks; the effect was greatest at the shortest duration. A subset of patients also underestimated intervals. Cerebellar patients were significantly more variable on the estimation and reproduction tasks. No significant differences between normal and cerebellar patients were found on temporal discrimination tasks with either sub- or suprasecond times. Patients with damage to the lateral superior hemispheres or the dentate nuclei showed more significant impairments than those with damage elsewhere in the cerebellum, and patients with damage to the left cerebellum had more significant differences from controls than those with damage to the right. These data suggest that damage to the middle-to-superior lobules or the left hemisphere is especially detrimental to timing suprasecond intervals. We suggest that this region be considered part of a network of brain structures including the DLPFC that is crucial for interval timing.     

Metabolic Changes of Cerebrum by Repetitive Transcranial Magnetic Stimulation over Lateral Cerebellum: A Study with FDG PET

To better understand the functional role of cerebellum within the large-scale cerebellocerebral neural network, we investigated the changes of neuronal activity elicited by cerebellar repetitive transcranial magnetic stimulation (rTMS) using (18)F-fluorodeoxyglucose (FDG) and positron emission tomography (PET). Twelve right-handed healthy volunteers were studied with brain FDG PET under two conditions: active rTMS of 1?Hz frequency over the left lateral cerebellum and sham stimulation. Compared to the sham condition, active rTMS induced decreased glucose metabolism in the stimulated left lateral cerebellum, the areas known to be involved in voluntary motor movement (supplementary motor area and posterior parietal cortex) in the right cerebral hemisphere, and the areas known to be involved in cognition and emotion (orbitofrontal, medial frontal, and anterior cingulate gyri) in the left cerebral hemisphere. Increased metabolism was found in cognition- and language-related brain regions such as the left inferior frontal gyrus including Broca's area, bilateral superior temporal gyri including Wernicke's area, and bilateral middle temporal gyri. Left cerebellar rTMS also led to increased metabolism in the left cerebellar dentate nucleus and pons. These results demonstrate that rTMS over the left lateral cerebellum modulates not only the target region excitability but also excitability of remote, but interconnected, motor-, language-, cognition-, and emotion-related cerebral regions. They provide further evidence that the cerebellum is involved not only in motor-related functions but also in higher cognitive abilities and emotion through the large-scale cerebellocereberal neural network.     

The role of the cerebellum in 'real' and 'imaginary' line bisection explored with 1-Hz repetitive transcranial magnetic stimulation

The role of the cerebellum is well characterized for many motor processes and for some cognitive tasks, although its contribution to lateralized spatial judgement has never been probed directly. To address this omission, we investigated the effects of cerebellar disruption on two different line bisection tasks in eight healthy subjects. Based on previous evidence of crossed cerebellar-cortical connections we predicted a shift in the perceived midline that would occur in opposite directions depending on the cerebellar hemisphere targeted. Repetitive transcranial magnetic stimulation (rTMS), given at 1-Hz (600 pulses), was used as a non-invasive way to interfere with processing in the cerebellar cortex. Performance was assessed for both 'physical' line bisection using a newly developed Landmark variant task and for 'mental' line bisection using number pairs. The effects for number line bisection were lateralized--left but not right cerebellar rTMS increased rightward errors, whereas for physical line bisection rTMS to either hemisphere did not affect performance. Effects due to neck muscle contraction and changes in eye position were ruled out with appropriate control stimulation sites, and eye-tracking. The results confirm the role of the cerebellum in spatial judgement, and, for the first time, demonstrate direct cerebellar involvement in the generation of the midline in 'imaginal' (number) space. The difference between number line and physical line bisection effects is discussed with reference to pre-existing models of cerebellar hemispheric specialization and functional topography.     

Role of the cerebellum in time perception: a TMS study in normal subjects

The aim of this study was to investigate the role of the cerebellum in a temporal-discrimination task without movement production in healthy subjects. Ten healthy subjects underwent a time-perception task with somatosensory stimuli. Two pairs of electrical stimuli: the first considered the reference pair (rp) with a standard interval of 400 ms and the second, the test pair (tp), with variable intervals ranging from 300 to 500 ms, were applied by surface electrodes on the right forearm. Subjects were instructed to compare time intervals of rp and tp and to estimate whether the tp interval was shorter than, equal to, or longer than that of rp. The task was performed in baseline and after 1 Hz rTMS over the right and left cerebellar hemisphere. The right cerebellar rTMS worsened temporal discrimination of cutaneous somatosensory electrical stimuli on the ipsilateral hand. rTMS of the left cerebellar hemisphere did not determine significant changes in the subjects' performance with respect to the baseline. These findings suggest that the cerebellum plays a role in merely perceptive aspects of temporal information processing.     

How does one night of sleep deprivation affect the internal clock?

Twelve subjects performed two temporal tasks, one explicit (Experiment 1) and one implicit (Experiment 2) after one night of sleep deprivation and after one night of normal rest. Experiment 1 involved a 1100-ms duration production task, and in Experiment 2 subjects performed a word identification task requiring implicit estimation of vowel duration (around 150 ms). One night of sleep deprivation had the same pattern of effect on explicit timing in the suprasecond range and implicit timing in the millisecond range. Specifically, sleep deprivation induced productions of shorter intervals in the duration production task and estimation of segmental durations as being longer in the word identification task. Both results are consistent with an acceleration of pacemaker rate.Moreover, in both experiments, we found a correlation between the alertness level of participants and the size of the effect. Therefore, sleep deprivation, which physiologically manipulates cortical arousal level, produced similar performance modulation in suprasecond explicit and subsecond implicit tasks suggesting a common mechanism.     

Is the Cerebellum a Potential Target for Stimulation in Parkinson's Disease? Results of 1-Hz rTMS on Upper Limb Motor Tasks

The aim of this study was to find whether 1-Hz cerebellar repetitive transcranial magnetic stimulation (rTMS) could affect upper limb movement in early-stage Parkinson's disease (PD). Twenty patients with PD underwent one session with real and one with sham rTMS. rTMS (1 Hz, 600 pulses) was targeted at the right lateral cerebellum. Before and after rTMS, patients performed two motor tests with their fingers and hands (ball test, nine-hole peg test). The duration of these tests was measured. There were statistically significant differences (p < 0.05) in the results of the tests after real stimulation and sham stimulation. We excluded the impact of learning. After real rTMS, we observed a significantly faster response in the ball test and a slower response in the nine-hole peg test, both on the right upper limb. This study indicates the influence of 1-Hz cerebellar rTMS in modifying the voluntary movements of the upper limb in PD. This influence is differentiated: the improvement of gross motor skills and the worsening of fine motor skills.     

High-frequency repetitive transcranial magnetic stimulation to the cerebellum and implicit processing of happy facial expressions

Background

Previous research has demonstrated that the cerebellum is involved in emotive and cognitive processes. Furthermore, recent findings suggest high-frequency repetitive transcranial magnetic stimulation (rTMS) to the cerebellum has mood-improving properties. We sought to further explore the effects of cerebellar high-frequency rTMS on implicit processing of emotional stimuli and mood.

Methods

In a double-blind, crossover study, 15 healthy volunteers received 15 minutes of 20 Hz (5 s on, 5 s off) rTMS over the medial cerebellum, occipital cortex or sham in a randomized counterbalanced order on 3 consecutive days. A masked emotional faces response task measured implicit emotional processing of happy, fearful and neutral facial expressions. We used positive and negative affect scales to evaluate rTMS-related changes in mood.

Results

High-frequency rTMS over the cerebellum was associated with significant increases in masked emotional responses to happy facial expressions only. We observed no changes in consciously experienced mood.

Limitations

Although the sham rTMS served as our baseline measurement, additional pre-rTMS data showing that reaction time increases immediately after cerebellar rTMS would have made our results more compelling.

Conclusion

The results replicate and extend previous findings by establishing a direct relation between the cerebellum and emotive information-processing. The parallel between the present effects of high-frequency cerebellar rTMS and short-term antidepressant therapy regarding the change in implicit processing of positive stimuli in the absence of mood changes is notable and warrants further research.     

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 patient's 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.     

Early Trajectory Prediction in Elite Athletes

Cerebellar plasticity is a critical mechanism for optimal feedback control. While Purkinje cell activity of the oculomotor vermis predicts eye movement speed and direction, more lateral areas of the cerebellum may play a role in more complex tasks, including decision-making. It is still under question how this motor-cognitive functional dichotomy between medial and lateral areas of the cerebellum plays a role in optimal feedback control. Here we show that elite athletes subjected to a trajectory prediction, go/no-go task manifest superior subsecond trajectory prediction accompanied by optimal eye movements and changes in cognitive load dynamics. Moreover, while interacting with the cerebral cortex, both the medial and lateral cerebellar networks are prominently activated during the fast feedback stage of the task, regardless of whether or not a motor response was required for the correct response. Our results show that cortico-cerebellar interactions are widespread during dynamic feedback and that experience can result in superior task-specific decision skills.     

Interference of left and right cerebellar rTMS with procedural learning

Increasing evidence suggests cerebellar involvement in procedural learning. To further analyze its role and to assess whether it has a lateralized influence, in the present study we used a repetitive transcranial magnetic stimulation interference approach in a group of normal subjects performing a serial reaction time task. We studied 36 normal volunteers: 13 subjects underwent repetitive transcranial magnetic stimulation on the left cerebellum and performed the task with the right (6 subjects) or left (7 subjects) hand; 10 subjects underwent repetitive transcranial magnetic stimulation on the right cerebellum and performed the task with the hand ipsilateral (5 subjects) or contralateral (5 subjects) to the stimulation; another 13 subjects served as controls and were not submitted to repetitive transcranial magnetic stimulation; 7 of them performed the task with the right hand and 6 with the left hand. The main results show that interference with the activity of the lateral cerebellum induces a significant decrease of procedural learning: Interference with the right cerebellar hemisphere activity induces a significant decrease in procedural learning regardless of the hand used to perform the serial reaction time task, whereas left cerebellar hemisphere activity seems more linked with procedural learning through the ipsilateral hand. In conclusion, the present study shows for the first time that a transient interference with the functions of the cerebellar cortex results in an impairment of procedural learning in normal subjects and it provides new evidences for interhemispheric differences in the lateral cerebellum.     

Performance consistency of normal observers in forced-choice tachistoscopic visual line bisection.

Pseudoneglect (PN) refers to the leftward error exhibited by normal observers on line bisection tasks (Bowers and Heilman, Neuropsychologia, 18, (1980) 491-8). Although a thorough review of the literature has shown PN to be relatively robust (Jewell and McCourt, Neuropsychologia, 38, (2000) 93-110), controversy remains concerning the reliability of the phenomenon, with some studies reporting a relatively high incidence of normal subjects with rightward bisection errors. The present experiment assesses the consistency of bisection performance in normal young observers. Right-handed subjects (N=22) participated in a tachistoscopic forced-choice line bisection task. Each subject participated in 7-16 experimental sessions separated by at least 24 h (total bisection measurements=317). Individual bisection performance could thus be evaluated with respect to within-subject variability measures. An eyetracker recorded gaze position during the task in one session. A highly significant mean group bisection error of -0.26 degrees (P<0.001) was obtained (left negative), and individual subject means ranged from -0.55 degrees to +0.03 degrees. Of the 317 total bisection measurements, 9% (28) deviated rightward. Significant (P<0.05) mean leftward errors occurred in 91% (20/22) of subjects. Mean bisection error in two subjects was not significantly different from zero. No subject possessed a significant rightward error. Mean gaze deviation from screen (and line) center ranged from +/-0.9 degrees, and was positively correlated (P<0.05) with bisection error. It is concluded that forced-choice tachistoscopic line bisection measures are highly reliable; a mean correlation of +0.87 exists between mean error based on 15 trials and means estimated from a random sample of only two trials. The incidence of true rightward bisection error in the population of normal right-handed subjects is thus estimated to be less than 5%.     

Sensorimotor integration for speech motor learning involves the inferior parietal cortex

Sensorimotor integration is important for motor learning. The inferior parietal lobe, through its connections with the frontal lobe and cerebellum, has been associated with multisensory integration and sensorimotor adaptation for motor behaviors other than speech. In the present study, the contribution of the inferior parietal cortex to speech motor learning was evaluated using repetitive transcranial magnetic stimulation (rTMS) prior to a speech motor adaptation task. Subjects' auditory feedback was altered in a manner consistent with the auditory consequences of an unintended change in tongue position during speech production, and adaptation performance was used to evaluate sensorimotor plasticity and short-term learning. Prior to the feedback alteration, rTMS or sham stimulation was applied over the left supramarginal gyrus (SMG). Subjects who underwent the sham stimulation exhibited a robust adaptive response to the feedback alteration whereas subjects who underwent rTMS exhibited a diminished adaptive response. The results suggest that the inferior parietal region, in and around SMG, plays a role in sensorimotor adaptation for speech. The interconnections of the inferior parietal cortex with inferior frontal cortex, cerebellum and primary sensory areas suggest that this region may be an important component in learning and adapting sensorimotor patterns for speech.     

Fear conditioned potentiation of the acoustic blink reflex in patients with cerebellar lesions

OBJECTIVE: To investigate whether the human cerebellum takes part in fear conditioned potentiation of the acoustic blink reflex. METHODS: A group of 10 cerebellar patients (eight patients with lesions involving the medial cerebellum, two patients with circumscribed lesions of the cerebellar hemispheres) was compared with a group of 16 age and sex matched healthy control subjects. The fear conditioned potentiation paradigm consisted of three phases. During the first, habituation phase subjects received 20 successive acoustic blink stimuli. In the subsequent fear conditioning phase, subjects passed through 20 paired presentations of the unconditioned fear stimulus (US; an electric shock) and the conditioned stimulus (CS; a light). Thereafter, subjects underwent the potentiation phase, which consisted of a pseudorandom order of 12 trials of the acoustic blink stimulus alone, 12 acoustic blink stimuli paired with the conditioned stimulus, and six conditioned stimuli paired with the unconditioned stimulus. The EMG of the acoustic blink reflex was recorded at the orbicularis oculi muscles. The potentiation effect was determined as the difference in normalised peak amplitude of the blink reflex evoked by pairs of CS and acoustic blink stimuli and evoked by the acoustic stimulus alone. RESULTS: In the habituation phase, short term habituation of the acoustic blink reflex was preserved in all cerebellar patients. However, in the potentiation phase, the potentiation effect of the blink reflex was significantly reduced in patients with medial cerebellar lesions compared with the controls (mean (SD) potentiation effect (%), patients: -6.4 (15.3), controls: 21.6 (35.6)), but was within normal limits in the two patients with lateral lesions. CONCLUSIONS: The present findings suggest that the human medial cerebellum is involved in associative learning of non-specific aversive reactions-that is, the fear conditioned potentiation of the acoustic blink reflex.     

Pseudoneglect: a review and meta-analysis of performance factors in line bisection tasks

An exhaustive qualitative (vote-counting) review is conducted of the literature concerning visual and non-visual line bisection in neurologically normal subject populations. Although most of these studies report a leftward bisection error (i.e., pseudoneglect), considerable between-study variability and inconsistency characterize this literature. A meta-analysis of this same literature is performed in which the total quantitative data set, comprising 73 studies (or sub-studies) and 2191 subjects, is analyzed with respect to 26 performance factors. The meta-analytic results indicate a significant leftward bisection error in neurologically normal subjects, with an overall effect size of between -0.37 and -0.44 (depending on integration method), which is significantly modulated to varying degrees by a number of additional task or subject variables. For example, visual bisection tasks, midsagittal-pointing tasks and tactile bisection tasks all lead to leftward errors, while kinesthetic tasks result in rightward errors. Tachistoscopic forced-choice testing methods reveal much greater estimates of bisection error (effect size = -1.32) than do manual method-of-adjustment procedures (effect size= -0.40). Subject age significantly modulates line bisection performance such that older subjects err significantly rightward compared to younger subjects, and to veridical line midpoint. Male subjects make slightly larger leftward errors than do female subjects. Handedness has a small effect on bisection errors, with dextrals erring slightly further to the left than sinistral subjects. The hand used to perform manual bisection tasks modulated performance, where use of the left hand lead to greater leftward errors than those obtained using the right hand. One of the most significant factors modulating bisection error is the direction in which subjects initiate motor scanning (with either eye or hand), where a left-to-right scan pattern leads to large leftward errors while a right-to-left scan pattern leads to rightward errors.     

Non‐invasive magnetic stimulation of the human cerebellum facilitates cortico‐bulbar projections in the swallowing motor system

Background Animal and human brain imaging studies suggest that the cerebellum plays an important role in the control of swallowing. In this study, we probed the interaction between cerebellar and pharyngeal motor cortical activity with transcranial magnetic stimulation (TMS) to determine if the cerebellum can modulate cortical swallowing motor circuitry. Methods Healthy volunteers (n = 16, eight men, mean age = 32, range 19–57 years) underwent TMS measurements of pharyngeal electromyography (EMG) recorded from a swallowed intraluminal catheter to assess cortical and cerebellar excitability. Subjects then underwent a paired pulse paradigm, where active or sham TMS conditioning pulses over the cerebellum and control sites were followed by suprathreshold TMS over the cortical pharyngeal area. Paired pulses were delivered at varying inter‐stimulus intervals (ISIs) with the cortical response amplitudes being assessed. Key Results Stimulation of the cerebellum over its midline or hemispheres evoked distinct pharyngeal EMG responses. There was no difference in EMG amplitudes following cerebellar hemispheric or midline stimulation (mean 55.5 ± 6.9 vs 42.8 ± 5.9 μV, P = 0.08). In contrast, after cerebellar preconditioning, the cortically evoked responses underwent maximal facilitation at ISIs of 50–200 ms (P < 0.05), an effect not seen with sham or trigeminal nerve preconditioning. Conclusions & Inferences Posterior fossa stimulation excites the cerebellum and evokes direct motor responses within the pharynx. When conditioned with TMS, the cerebellum strongly facilitates the cortical swallowing motor pathways. This finding suggests that the cerebellum exerts a modulatory effect on human swallowing and raises the possibility that excitatory neurostimulation of the cerebellum may be therapeutically useful in promoting recovery of dysphagia after neural damage.     

Losing my hand. Body ownership attenuation after virtual lesion of the primary motor cortex

A fundamental component of the self‐awareness is the sensation that we are acting with our own body. Thus, a coherent sense of self implies the existence of a tight link between the sense of body ownership and the motor system. Here, we investigated this issue by taking advantage of a well‐known experimental manipulation of body ownership, i.e., the rubber hand illusion (RHI), during which the subjects perceive a fake hand as part of their own body. To test the effect of the motor system down‐regulation on the RHI susceptibility, we designed a sham‐controlled study, where the primary motor cortex (M1) excitability was modulated by off‐line low‐frequency repetitive transcranial magnetic stimulation (rTMS). After rTMS (real or sham), subjects underwent the RHI either on the right hand, contralateral to the inhibited hemisphere (Experiment 1), or on the left hand, ipsilateral to the inhibited hemisphere (Experiment 2). Only in Experiment 1, the procedure strengthened the illusory experience, as proved by a significant increase, in rTMS compared to Sham, of both subjective (Embodiment/Disembodiment Questionnaires) and objective (Proprioceptive Drift) RHI measures. This evidence demonstrates that, when the M1 activity is down‐regulated, the sense of body ownership is attenuated and the subjects become more prone to incorporate an alien body part. This, in turn, supports the existence of a mutual interaction between the sense of body ownership and the motor system, shedding new light on the construction of a coherent sense of self as an acting body.     

Left prefrontal-repetitive transcranial magnetic stimulation (rTMS) and regional cerebral glucose metabolism in normal volunteers

Repetitive transcranial magnetic stimulation (rTMS) holds promise as a probe into the pathophysiology and possible treatment of neuropsychiatric disorders. To explore its regional effects, we combined rTMS with positron emission tomography (PET). Fourteen healthy volunteers participated in a baseline 18-fluorodeoxyglucose (FDG) PET scan. During a second FDG infusion on the same day, seven subjects received 30 min of 1 Hz rTMS at 80% of motor threshold to left prefrontal cortex, and seven other subjects received sham rTMS under identical conditions. Global and normalized regional cerebral glucose metabolic rates (rCMRglu) from the active and sham conditions were compared to baseline and then to each other. Sham, but not active 1 Hz rTMS, was associated with significantly increased global CMRglu. Compared to baseline, active rTMS induced normalized decreases in rCMRglu in right prefrontal cortex, bilateral anterior cingulate, basal ganglia (L>R), hypothalamus, midbrain, and cerebellum. Increases in rCMRglu were seen in bilateral posterior temporal and occipital cortices. Sham rTMS compared to baseline resulted in isolated normalized decreases in rCMRglu in left dorsal anterior cingulate and left basal ganglia, and increases in posterior association and occiptal regions. Differences between the 1 Hz active versus sham changes from baseline revealed that active rTMS induced relative decrements in rCMRglu in the left superior frontal gyrus and increases in the cuneus (L>R). One Hertz rTMS at 80% motor threshold over the left prefrontal cortex in healthy subjects compared to sham rTMS in another group (each compared to baseline) induced an area of decreased normalized left prefrontal rCMRglu not directly under the stimulation site, as well as increases in occipital cortex. While these results are in the predicted direction, further studies using other designs and higher intensities and frequencies of rTMS are indicated to better describe the local and distant changes induced by rTMS.     

Cerebellar involvement in timing accuracy of rhythmic finger movements in essential tremor

The cerebellum is involved in the generation of essential tremor (ET) and cerebellar timing function is altered in patients with ET showing an increased variability of rhythmic hand movements. Using a sensor‐engineered glove, we evaluated motor behaviour during repetitive finger tapping movements in 15 patients with ET and in 11 age‐ and gender‐matched normal subjects. In addition, we investigated whether, in patients with ET, an inhibitory repetitive transcranial magnetic stimulation (1 Hz‐rTMS) over lateral cerebellum was able to change timing properties and motor behaviour. Patients with ET showed a longer touch duration (TD) and a lower inter tapping interval (ITI) than normal subjects. The temporal variability of the movement (coefficient of variation of ITI) was increased in patients with ET. Neither clinical rating scale or tremor measurements correlated with any parameter of motor performance in the ET group. 1 Hz‐rTMS over ipsilateral lateral cerebellum transiently affected the performance of patients with ET, by reducing TD values and normalizing ITI values. After 1 Hz‐rTMS, the coefficient of variation of ITI was restored to values similar to those of normal subjects. We postulate that the strategy to increase TD, probably adopted to allow a better perception of movement, can affect ITI and its variability. The results support the idea that the cerebellum plays a central role in the selection of motor strategy of rhythmic finger movements, particularly in terms of temporal organization of movement.     

Deep TMS of the insula using the H-coil modulates dopamine release: a crossover [<Superscript>11</Superscript>C] PHNO-PET pilot trial in healthy humans

Modulating the function of the insular cortex could be a novel therapeutic strategy to treat addiction to a variety of drugs of abuse as this region has been implicated in mediating drug reward and addictive processes. The recent advent of the H-coil has permitted the targeting of deeper brain structures which was not previously feasible. The goal of this study was to bilaterally target the insular region using the H-coil with repetitive Transcranial Magnetic Stimulation (rTMS) and subsequently measure changes in dopamine levels using Positron Emission Tomography (PET) with [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO). This was a within-subject, crossover, blinded and sham-controlled pilot study. Eight healthy, right-handed subjects, aged 19–45, participated in the investigation. All subjects underwent 3 PHNO-PET scans preceded by rTMS (sham, 1 Hz or 10 Hz), on 3 separate days. Low frequency rTMS (1 Hz), targeting the insular cortex, significantly decreased dopamine levels in the substantia nigra, sensorimotor striatum and associative striatum. Replicating this study in tobacco smokers or alcoholics would be a logical follow-up to assess whether H-coil stimulation of the bilateral insula can be employed as a treatment option for addiction. Trial registration: NCT02212405     

Parietal rTMS distorts the mental number line: simulating 'spatial' neglect in healthy subjects

Patients with left-sided visuospatial neglect, typically after damage to the right parietal lobe, show a systematic bias towards larger numbers when asked to bisect a numerical interval. This has been taken as further evidence for a spatial representation of numbers, perhaps akin to a mental number line with smaller numbers represented to the left and larger numbers to the right. Previously, contralateral neglect-like symptoms in physical line bisection have been induced in healthy subjects with repetitive transcranial magnetic stimulation (rTMS) over right posterior parietal lobe. Here we used rTMS over parietal and occipital sites in healthy subjects to investigate spatial representations in a number bisection task. Subjects were asked to name the midpoint of numerical intervals without calculating. On control trials subjects' behaviour was similar to performance reported in physical line bisection experiments. Subjects underestimated the midpoint of the numerical interval. Repetitive transcranial magnetic stimulation produced representational neglect-like symptoms in number bisection when applied over right posterior parietal cortex (right PPC). Repetitive TMS over right PPC shifted the perceived midpoint of the numerical interval significantly to the right while occipital TMS had no effect on bisection performance. Our study therefore provides further evidence that subjects use spatial representations, perhaps akin to a mental number line, in basic numerical processing tasks. Furthermore, we showed that the right posterior parietal cortex is crucially involved in spatial representation of numbers.