Enhancing neuroplasticity in major depression: A novel 10 Hz-rTMS protocol is more effective than iTBS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment in major depressive disorder (MDD). However, intermittent theta-burst stimulation (iTBS) and rTMS protocols using 10 Hz stimulation frequency might differ in their effect on neuroplasticity and on clinical symptoms. This study compares the effect of iTBS and a novel 10 Hz-rTMS with shortened single session duration, on motor excitability and neuroplasticity and on clinical symptoms in MDD. METHODS: 30 patients with MDD received either iTBS or the novel 10 Hz-rTMS daily over three weeks to the left dorsolateral prefrontal cortex. Before and after the interventions, motor excitability, short-latency intracortical inhibition and long-term-potentiation-like plasticity in the motor cortex and clinical symptoms were measured by use of transcranial magnetic stimulation. RESULTS: After the intervention, the level of neuroplasticity increased and clinical symptoms of depression were reduced in both groups, though both effects were significantly stronger after the novel 10 Hz-rTMS. Importantly, the changes in neuroplasticity and clinical symptoms were correlated: the stronger neuroplasticity increased, the stronger was the improvement of clinical symptoms. LIMITATIONS: Short intervention period of 3 weeks. Clinical symptoms were measured by self-assessment only and are therefore preliminary. CONCLUSIONS: The novel 10 Hz-rTMS is more effective in increasing neuroplasticity in MDD and potentially also in reducing clinical symptoms than iTBS. This might be due to a differential mode of action on neuroplasticity and to the stimulation frequency of 10 Hz (within the alpha range) being more suitable to reset the brain's activity and to support neuroplastic changes.

Physical Activity Reduces Clinical Symptoms and Restores Neuroplasticity in Major Depression.

Major depressive disorder (MDD) is the most common mental disorder and deficits in neuroplasticity are discussed as one pathophysiological mechanism. Physical activity (PA) enhances neuroplasticity in healthy subjects and improves clinical symptoms of MDD. However, it is unclear whether this clinical effect of PA is due to restoring deficient neuroplasticity in MDD. We investigated the effect of a 3-week PA program applied on clinical symptoms, motor excitability and plasticity, and on cognition in patients with MDD (N = 23), in comparison to a control intervention (CI; N = 18). Before and after the interventions, the clinical symptom severity was tested using self- (BDI-II) and investigator- (HAMD-17) rated scales, transcranial magnetic stimulation (TMS) protocols were used to test motor excitability and paired-associative stimulation (PAS) to test long-term-potentiation (LTP)-like plasticity. Additionally, cognitive functions such as attention, working memory and executive functions were tested. After the interventions, the BDI-II and HAMD-17 decreased significantly in both groups, but the decrease in HAMD-17 was significantly stronger in the PA group. Cognition did not change notably in either group. Motor excitability did not differ between the groups and remained unchanged by either intervention. Baseline levels of LTP-like plasticity in the motor cortex were low in both groups (PA: 113.40 ± 2.55%; CI: 116.83 ± 3.70%) and increased significantly after PA (155.06 ± 10.48%) but not after CI (122.01 ± 4.1%). Higher baseline BDI-II scores were correlated with lower levels of neuroplasticity. Importantly, the more the BDI-II score decreased during the interventions, the stronger did neuroplasticity increase. The latter effect was particularly strong after PA (r = -0.835; p < 0.001). The level of neuroplasticity related specifically to the psychological/affective items, which are tested predominantly in the BDI-II. However, the significant clinical difference in the intervention effects was shown in the HAMD-17 which focuses more on somatic/neurovegetative items known to improve earlier in the course of MDD. In summary, PA improved symptoms of MDD and restored the deficient neuroplasticity. Importantly, both changes were strongly related on the individual patients' level, highlighting the key role of neuroplasticity in the pathophysiology and the clinical relevance of neuroplasticity-enhancing interventions for the treatment of MDD.

Task specific dystonia - a patients' perspective.

BACKGROUND: Task specific dystonia (TSD) is a subtype of dystonia with no cure and significant limitations on treatments. Few studies have investigated the outcomes of rehabilitative therapy from the patient's perspective. PURPOSE OF THE STUDY: This study explored the interventions that patients have utilized and their perceived effectiveness in treating and managing their TSD, specifically musicians' dystonia (MD) and writer's dystonia (WD). Symptoms and the effect of TSD on the perceived performance of every day and specific tasks, and possible reasons why the condition developed, were also investigated. STUDY DESIGN: Descriptive survey. METHODS: Patients diagnosed with TSD, treated at a private hand therapy unit, who had consented to being contacted for research purposes, were emailed a link to an online survey (or posted if email was not available), administered via KwikSurveys. The survey consisted of 4 subsections: personal information, general medical history, dystonia medical history and dystonia treatment history. RESULTS: Invitations were sent to 105 patients of whom 90% (n = 95/105) responded. Results for both the MD and WD groups were similar. There was a significant association between the 2 groups as to what they viewed may have led to the development of TSD (a change in technique; P < .001) and the most effective treatments (massage P< .043, modifications to the instrument P< .002; ultrasound therapy P< .013.) All reported that daily activities were affected by their condition. DISCUSSION: Although full levels of task specific function (playing their instrument or writing) were not usually regained, participants with both MD and WD perceived improvement in symptoms with rehabilitation intervention. Three treatments were perceived to be most effective in achieving this, suggesting that these should be considered for inclusion within treatment plans. CONCLUSIONS: From the perspective of people with TSD, a range of rehabilitation interventions are effective in enhancing symptom management, providing further evidence to support their use.

Intensity dependent effect of cognitive training on motor cortical plasticity and cognitive performance in humans.

Intervention-induced neuroplastic changes within the motor or cognitive system have been shown in the human brain. While cognitive and motor brain areas are densely interconnected, it is unclear whether this interconnectivity allows for a shared susceptibility to neuroplastic changes. Using the preparation for a theoretical exam as training intervention that primarily engages the cognitive system, we tested the hypothesis whether neuroplasticity acts across interconnected brain areas by investigating the effect on excitability and synaptic plasticity in the motor cortex. 39 healthy students (23 female) underwent 4 weeks of cognitive training while revision time, physical activity, concentration, fatigue, sleep quality and stress were monitored. Before and after cognitive training, cognitive performance was evaluated, as well as motor excitability using transcranial magnetic stimulation and long-term-potentiation-like (LTP-like) plasticity using paired-associative-stimulation (PAS). Cognitive training ranged individually from 1 to 7 h/day and enhanced attention and verbal working memory. While motor excitability did not change, LTP-like plasticity increased in an intensity-depending manner: the longer the daily revision time, the smaller the increase of neuroplasticity, and vice versa. This effect was not influenced by physical activity, concentration, fatigue, sleep quality or stress. Motor cortical plasticity is strengthened by a behavioural intervention that primarily engages cognitive brain areas. We suggest that this effect is due to an enhanced susceptibility to LTP-like plasticity, probably induced by heterosynaptic activity that modulates postsynaptic excitability in motorcortical neurones. The smaller increase of PAS efficiency with higher cognitive training intensity suggests a mechanism that balances and stabilises the susceptibility for synaptic potentiation.

Sensorimotor deprivation induces interdependent changes in excitability and plasticity of the human hand motor cortex.

Prolonged limb immobilization deprives sensorimotor cortical areas of an important source of excitatory input, as well as of motor output. Previous work has described effects on motor excitability but it is unclear whether motor plasticity is also influenced. In two groups of eight healthy human subjects, the left hand was immobilized for 8 h to induce sensorimotor deprivation of the cortical representation of the abductor pollicis brevis muscle. We used transcranial magnetic stimulation protocols to evaluate motor excitability with motor-evoked potentials, input-output (IOcurve) and short-latency intracortical inhibition (SICI) recruitment curves, as well as long-term potentiation (LTP)/long-term depression (LTD)-like plasticity with paired-associative stimulation (PAS) of the median nerve and motor cortex using an interstimulus interval of 25 ms (PAS25) or 10 ms (PAS10), respectively, in two sessions at least 7 d apart (baseline and after immobilization). After immobilization, the slope of the IOcurve decreased, and SICI at lower conditioning pulse intensities was reduced. The LTP-like effects of PAS25 and the LTD-like effect of PAS10 were both significantly enhanced. The effects differed among individuals: the more IOslope decreased after immobilization, the greater the increase of PAS25 and the smaller the increase of PAS10 effects. We suggest that sensorimotor deprivation has two effects. It increases the sensitivity to remaining sensory inputs and therefore increases the effectiveness of both PAS protocols. In addition, it reduces neuronal excitability to an individually different level, as reflected in the reduced IOslope and leads to an interdependent modulation of synaptic plasticity as such as it shifts the threshold of LTP/LTD-like plasticity induction.

The in-the-ear recording concept: user-centered and wearable brain monitoring.

The integration of brain monitoring based on electroencephalography (EEG) into everyday life has been hindered by the limited portability and long setup time of current wearable systems as well as by the invasiveness of implanted systems (e.g. intracranial EEG). We explore the potential to record EEG in the ear canal, leading to a discreet, unobtrusive, and user-centered approach to brain monitoring. The in-the-ear EEG (Ear-EEG) recording concept is tested using several standard EEG paradigms, benchmarked against standard onscalp EEG, and its feasibility proven. Such a system promises a number of advantages, including fixed electrode positions, user comfort, robustness to electromagnetic interference, feedback to the user, and ease of use. The Ear-EEG platform could also support additional biosensors, extending its reach beyond EEG to provide a powerful health-monitoring system for those applications that require long recording periods in a natural environment.

Modulation of proprioceptive integration in the motor cortex shapes human motor learning.

Sensory and motor systems interact closely during movement performance. Furthermore, proprioceptive feedback from ongoing movements provides an important input for successful learning of a new motor skill. Here, we show in humans that attention to proprioceptive input during a purely sensory task can influence subsequent learning of a novel motor task. We applied low-amplitude vibration to the abductor pollicis brevis (APB) muscle of eight healthy volunteers for 15 min while they discriminated either a small change in vibration frequency or the presence of a simultaneous weak cutaneous stimulus. Before and after the sensory attention tasks, we evaluated the following in separate experiments: (1) sensorimotor interaction in the motor cortex by testing the efficacy of proprioceptive input to reduce GABA(A)ergic intracortical inhibition using paired-pulse transcranial magnetic stimulation, and (2) how well the same subjects learned a ballistic thumb abduction task using the APB muscle. Performance of the vibration discrimination task increased the interaction of proprioceptive input with motor cortex excitability in the APB muscle, whereas performance in the cutaneous discrimination task had the opposite effect. There was a significant correlation between the integration of proprioceptive input in the motor cortex and the motor learning gain: increasing the integration of proprioceptive input from the APB increased the rate of motor learning and reduced performance variability, while decreasing proprioceptive integration had opposite effects. These findings suggest that the sensory attention tasks transiently change how proprioceptive input is integrated into the motor cortex and that these sensory changes drive subsequent learning behavior in the human motor cortex.

Simultaneous intracranial EEG and fMRI of interictal epileptic discharges in humans.

Simultaneous scalp EEG-fMRI measurements allow the study of epileptic networks and more generally, of the coupling between neuronal activity and haemodynamic changes in the brain. Intracranial EEG (icEEG) has greater sensitivity and spatial specificity than scalp EEG but limited spatial sampling. We performed simultaneous icEEG and functional MRI recordings in epileptic patients to study the haemodynamic correlates of intracranial interictal epileptic discharges (IED). Two patients undergoing icEEG with subdural and depth electrodes as part of the presurgical assessment of their pharmaco-resistant epilepsy participated in the study. They were scanned on a 1.5 T MR scanner following a strict safety protocol. Simultaneous recordings of fMRI and icEEG were obtained at rest. IED were subsequently visually identified on icEEG and their fMRI correlates were mapped using a general linear model (GLM). On scalp EEG-fMRI recordings performed prior to the implantation, no IED were detected. icEEG-fMRI was well tolerated and no adverse health effect was observed. intra-MR icEEG was comparable to that obtained outside the scanner. In both cases, significant haemodynamic changes were revealed in relation to IED, both close to the most active electrode contacts and at distant sites. In one case, results showed an epileptic network including regions that could not be sampled by icEEG, in agreement with findings from magneto-encephalography, offering some explanation for the persistence of seizures after surgery. Hence, icEEG-fMRI allows the study of whole-brain human epileptic networks with unprecedented sensitivity and specificity. This could help improve our understanding of epileptic networks with possible implications for epilepsy surgery.

Present and future of simultaneous EEG-fMRI.

The brain's activity can be measured in numerous complementary ways, including electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). The simultaneous acquisition of EEG and fMRI was originally developed to make the localization of the generators of often subtle pathological activity commonly observed in EEG recordings of patients with epilepsy more sensitive and spatially accurate by mapping their hemodynamic correlates. Now, the value of the information provided by simultaneous EEG-fMRI is being evaluated in a clinical context, while in parallel, more sophisticated data analysis techniques, e.g. with electrical source imaging or dynamic causal modeling, have begun to be applied to increase the technique's sensitivity and allow the study of brain network structure. Beyond its clinically oriented application in epilepsy, simultaneous EEG-fMRI recording has now gained interest as a tool for basic and systems human neuroscience, e.g. the study of neuro-vascular coupling and cognitive studies. In this review, we give an overview over the current use of simultaneous EEG-fMRI, its applications to the study of epilepsy as well as human cognition and systems neuroscience and ongoing and anticipated methodological developments.

Regaining motor control in musician's dystonia by restoring sensorimotor organization.

Professional musicians are an excellent model of long-term motor learning effects on structure and function of the sensorimotor system. However, intensive motor skill training has been associated with task-specific deficiency in hand motor control, which has a higher prevalence among musicians (musician's dystonia) than in the general population. Using a transcranial magnetic stimulation paradigm, we previously found an expanded spatial integration of proprioceptive input into the hand motor cortex [sensorimotor organization (SMO)] in healthy musicians. In musician's dystonia, however, this expansion was even larger. Whereas motor skills of musicians are likely to be supported by a spatially expanded SMO, we hypothesized that in musician's dystonia this might have developed too far and now disrupts rather than assists task-specific motor control. If so, motor control should be regained by reversing the excessive reorganization in musician's dystonia. Here, we test this hypothesis and show that a 15 min intervention with proprioceptive input (proprioceptive training) restored SMO in pianists with musician's dystonia to the pattern seen in healthy pianists. Crucially, task-specific motor control improved significantly and objectively as measured with a MIDI (musical instrument digital interface) piano, and the amount of behavioral improvement was significantly correlated to the degree of sensorimotor reorganization. In healthy pianists and nonmusicians, the SMO and motor performance remained essentially unchanged. These findings suggest that the differentiation of SMO in the hand motor cortex and the degree of motor control of intensively practiced tasks are significantly linked and finely balanced. Proprioceptive training restored this balance in musician's dystonia to the behaviorally beneficial level of healthy musicians.

Consensus paper: use of transcranial magnetic stimulation to probe motor cortex plasticity in dystonia and levodopa-induced dyskinesia.

Plasticity includes the ability of the nervous system to optimize neuronal activity at a cellular and system level according to the needs imposed by the environment. Neuroplasticity phenomena within sensorimotor cortex are crucial to enhance function to increase skillfulness. Such plasticity may be termed "adaptive" to indicate its ecologically beneficial role. In professional musicians, enhanced adaptive plasticity is associated with one of the highest level of motor skill a human being can achieve and the amount of these changes is even dependent on the age at which instrumental playing was started. In addition, adaptive neuroplastic changes occur when nervous system try to repair itself thus compensating dysfunctions. However, when these adaptive phenomena are pushed to an extreme, they can produce a maladaptive sensorimotor reorganization that interferes with motor performance rather than improving it. The model we discuss here is focal hand dystonia I which an intrinsic abnormality of neural plasticity, in some predisposed individuals, may lead to abnormal sensorimotor integration and to the appearance of a characteristic movement disorder. Deficient homeostatic control might be an important mechanism triggering this maladaptive reorganization, and future behavioral studies are needed to confirm this hypothesis. In the second part of this consensus paper, we will critically discuss as a second model, the hypothesis that levodopa-induced dyskinesia correlate with an aberrant form of plasticity in the human primary motor cortex, possibly because of abnormal oscillations within the basal ganglia loop. Disorders of cortical plasticity have not in the past been considered as possible causes of human clinical states. The recognition that this can occur, together with a speculative mechanism, generates an important and provocative hypothesis for future research at the clinical-scientific interface.

Differential modulation of motor cortical plasticity and excitability in early and late phases of human motor learning.

Different phases of motor skill learning appear to involve different physiological processes, with long-term potentiation (LTP) occurring at existing synapses in early and cortical reorganization involving synaptogenesis in later phases. Here, we test the evolution of skill learning-dependent changes in motor plasticity and excitability in six subjects trained to perform rapid thumb abductions over 5 d. Plasticity was examined using paired-associative stimulation (PAS) of the median nerve and motor cortex to induce LTP-like "PAS given with an interstimulus interval of 25 ms (PAS25)" or long-term depression (LTD)-like "PAS given with an interstimulus interval of 10 ms (PAS10)" plasticity. Excitability was tested by measuring recruitment of motor-evoked-potentials "input-output (IO) curve" and of short-latency intracortical inhibition (SICI curve), and sensorimotor organization (SMO). Task performance improved continuously over 5 d. After practice on day 1, the PAS25 effect reversed from facilitation to inhibition whereas the slope of the IO curve increased and the level of SICI decreased. These effects on IO curve and SICI were still present or even enhanced before the last practice on day 5, and were not changed by it. The effect of proprioceptive input from the trained muscle on SMO was also strengthened before practice on day 5. In contrast, PAS-induced plasticity was not influenced by motor practice on day 5, and had returned to prepractice values. The interference with PAS-induced plasticity suggests that the initial performance improvement relies on increasing the efficacy of existing synaptic connections. However, the long-lasting changes in the IO curve, SICI curve, and SMO suggest that continued practice enhances performance by changing Motor cortical organization. We hypothesize that new synaptic connections might have formed that allow LTP/LTD-susceptibility to be restored without reducing synaptic strength and performance skill.

Motorcortical excitability and synaptic plasticity is enhanced in professional musicians.

Musicians not only have extraordinary motor and sensory skills, but they also have an increased ability to learn new tasks compared with non-musicians. We examined how these features are expressed in neurophysiological parameters of excitability and plasticity in the motor system by comparing the results of 11 professional musicians and 8 age-matched non-musicians. Parameters of motor excitability were assessed using transcranial magnetic stimulation (TMS) to measure motor-evoked potentials (MEPs) together with recruitment of corticospinal projections [input-output curve (IOcurve)] and of short-latency intracortical inhibition (SICIcurve). Plasticity, here defined as change of synaptic effectiveness, was tested by measuring MEPs and IOcurves after paired associative stimulation (PAS), which consists of an electric median nerve stimulus repeatedly paired (200 times at 0.25 Hz) with a TMS pulse over the hand motor area. Using an interstimulus interval of 25 ms (PAS25) or 10 ms (PAS10), this leads to long-term potentiation- or long-term depression-like plasticity, respectively. Musicians showed steeper recruitment of MEPs and SICI (IOcurve and SICIcurve). Additionally, PAS25 increased and PAS10 decreased the MEP amplitudes and the slope of the IOcurves significantly more in musicians than in non-musicians. This is consistent with a wider modification range of synaptic plasticity in musicians. Together with the steeper recruitment of corticospinal excitatory and intracortical inhibitory projections, this suggests that they regulate plasticity and excitability with a higher gain than normal. Because some of these changes depend on age at which instrumental playing commenced and on practice intensity, they may reflect an increase in number and modifiability of synapses within the motor area caused by long-term musical practice.

Transcallosal sensorimotor integration: effects of sensory input on cortical projections to the contralateral hand.

OBJECTIVE: Low amplitude vibration of forearm or hand muscles predominantly activates proprioceptive inputs that influence corticospinal projections in a focal manner, increasing output to the stimulated muscle while reducing output to neighbouring muscles. Modulation of contralateral forearm muscles by vibration has also been reported on one occasion. The aim of the current investigation was to investigate the effects of proprioceptive input from a hand muscle on corticospinal excitability, intracortical inhibition (SICI) and interhemispheric inhibition (IHI) targeting the homologous contralateral muscle. METHODS: Transcranial Magnetic Stimulation (TMS) was delivered to the left cortical hand area of 10 healthy subjects and surface electromyography (EMG) recordings taken from the right First Dorsal Interosseus (FDI) and Abductor Digiti Minimi (ADM). The effect of low amplitude vibration of the left FDI on MEP amplitudes, SICI and IHI targeting the right hand was assessed. RESULTS: Vibration of the left FDI caused a significant reduction in MEP amplitudes in the homologous right FDI but not in the right ADM. SICI and IHI targeting both muscles were also significantly increased. CONCLUSIONS: We conclude that proprioceptive input from a hand muscle reduces the corticospinal excitability of the contralateral homologous muscle. The increases in SICI and IHI suggest that at least some of this effect occurs in the cortex ipsilateral to the stimulus and this may be mediated via transcallosal fibres. SIGNIFICANCE: These results suggest that sensory input can modulate excitability in both motor cortices simultaneously, as well as the relationship between them. Interventions which modulate this transcallosal relationship may become useful in disorders where abnormal IHI is a potential therapeutic target.

Differences between the effects of three plasticity inducing protocols on the organization of the human motor cortex.

Several experimental protocols induce lasting changes in the excitability of motor cortex. Some involve direct cortical stimulation, others activate the somatosensory system and some combine motor and sensory stimulation. The effects usually are measured as changes in amplitude of the motor-evoked-potential (MEP) or short-interval intracortical inhibition (SICI) elicited by a single or paired pulses of transcranial magnetic stimulation (TMS). Recent work has also tested sensorimotor organization within the motor cortex by recording MEPs and SICI during short periods of vibration applied to single intrinsic hand muscles. Here sensorimotor organization is focal: MEPs increase and SICI decreases in the vibrated muscle, whilst the opposite occurs in neighbouring muscles. In six volunteers we compared the after effects of three protocols that lead to lasting changes in cortical excitability: (i) paired associative stimulation (PAS) between a TMS pulse and an electrical stimulus to the median nerve; (ii) motor practice of rapid thumb abduction; and (iii) sensory input produced by semicontinuous muscle vibration, on MEPs and SICI at rest and on the sensorimotor organization. PAS increased MEP amplitudes, whereas vibration changed sensorimotor organization. Motor practice had a dual effect and increased MEPs as well as affecting sensorimotor organization. The implication is that different protocols target different sets of cortical circuits. We speculate that protocols that involve repeated activation of motor cortical output lead to lasting changes in efficacy of synaptic connections in output circuits, whereas protocols that emphasize sensory inputs affect the strength of sensory inputs to motor circuits.

Spatial attention affects sensorimotor reorganisation in human motor cortex.

It is well known that the somatotopic representation of sensory and motor cortices reorganises in response to sustained changes in sensory input. It is also clear that the extent of the effect depends on whether or not subjects pay attention during the procedure. Here we show that the pattern of reorganisation produced by sustained sensory input depends not only on the subjects' attention but also on the spatial focus of their attention on the body surface. Maximal effects are observed only when subjects pay attention to the site of the input; if they attend to an adjacent body part then the effects are reduced. These results may be relevant to rehabilitation procedures commonly used in patients after stroke.

Pathophysiological differences between musician's dystonia and writer's cramp.

Focal hand dystonia (FHD) has been suggested to be a maladaptive response of the brain to repetitive performance of stereotyped and attentionally demanding hand movements. However, not all patients with FHD have a strict history of excessive hand use; for example, patients with musician's dystonia (MD) spend many hours per day with their attention focused on instrumental practice, whereas many patients with writer's cramp (WC) have a history of average hand use. The present experiments test whether seven MD and six WC patients have different pathophysiological deficits by examining the spatial pattern of sensorimotor organization in the motor cortex. Two control groups were used, eight healthy non-musicians and eight healthy musicians. The latter served to control for physiological adaptation of the brain to musical training. We used focal vibration of a single hand muscle to produce sensory input whilst the excitability of corticospinal outputs to the vibrated and other hand muscles was evaluated with transcranial magnetic stimulation. In healthy non-musicians, vibration increases the amplitude of motor-evoked potentials and decreases the short-latency intracortical inhibition (SICI) in the vibrated muscle, whilst having the opposite effect on the non-vibrated hand muscles. The pattern of sensorimotor interaction was abnormal in both patient groups. However, the nature of the deficit differed between them. While vibration had little effect on cortical excitability in WC, it strongly reduced SICI in all hand muscles irrespective of spatial organization in MD. In the healthy musicians we found an organization intermediate between that of healthy non-musicians and MD. The data are consistent with a model in which musical practice in healthy musicians leads to beneficial changes in organization of the motor cortex, but in MD these progress too far and begin to interfere with movement rather than assist it. The fact that sensory input had no effect on motor output in patients with WC suggests that sensory information from the hand may play a smaller role in provoking pathological changes in WC than in MD.

The right dorsolateral prefrontal cortex is essential in time reproduction: an investigation with repetitive transcranial magnetic stimulation.

This study used repetitive transcranial magnetic stimulation (rTMS) to investigate the roles of the right dorsolateral prefrontal cortex (DLPFC) and supplementary motor area (SMA) in short (500 ms) and long (2 s) interval timing. The results were compared with rTMS over the leg area of motor cortex, an area not thought to be involved with time estimation. rTMS was delivered during one of two phases of a time reproduction task: at the onset of the Estimation Phase (presentation of the interval to be timed) and at the onset of the Reproduction Phase (subjects' reproduction of the timed interval). There was a significant main effect of Site (SMA vs. right DLPFC vs. leg motor area) due to the fact that rTMS over the right DLPFC caused subjects to underestimate time intervals compared with rTMS over the leg motor area. There was also a significant three-way interaction between Site, Duration and Phase (Estimation Phase vs. Reproduction Phase) that post hoc analyses showed was due to underestimation of long intervals when rTMS was given over the right DLPFC at the start of the Reproduction Phase. There was no effect of rTMS over the right DLPFC or SMA in the short interval task. This is consistent with previous studies showing that the right DLPFC is important in estimating time intervals in the seconds-range. In addition, we suggest that the selectivity of the rTMS effect for the Reproduction Phase indicates that the right DLPFC plays a particular role in memory processes.