Combining transcranial magnetic stimulation with training to improve social cognition impairment in schizophrenia: a pilot randomized controlled trial.

Schizophrenia is a severe, chronic mental disorder that profoundly impacts patients' everyday lives. The illness's core features include positive and negative symptoms and cognitive impairments. In particular, deficits in the social cognition domain showed a tighter connection to patients' everyday functioning than the other symptoms. Social remediation interventions have been developed, providing heterogeneous results considering the possibility of generalizing the acquired improvements in patients' daily activities. In this pilot randomized controlled trial, we investigated the feasibility of combining fifteen daily cognitive and social training sessions with non-invasive brain stimulation to boost the effectiveness of the two interventions. We delivered intermittent theta burst stimulation (iTBS) over the left dorsolateral prefrontal cortex (DLPFC). Twenty-one patients were randomized into four groups, varying for the assigned stimulation condition (real vs. sham iTBS) and the type of cognitive intervention (training vs. no training). Clinical symptoms and social cognition tests were administered at five time points, i.e., before and after the treatment, and at three follow-ups at one, three, and six months after the treatments' end. Preliminary data show a trend in improving the competence in managing emotion in participants performing the training. Conversely, no differences were found in pre and post-treatment scores for emotion recognition, theory of mind, and attribution of intentions scores. The iTBS intervention did not induce additional effects on individuals' performance. The methodological approach's novelty and limitations of the present study are discussed.

Social Cognition Individualized Activities Lab for Social Cognition Training and Narrative Enhancement in Patients With Schizophrenia: A Randomized Controlled Study to Assess Efficacy and Generalization to Real-Life Functioning (Prot. n°: NCT05130853).

Subjects affected by schizophrenia present significant deficits in various aspects of social cognition, such as emotion processing, social perception and theory of mind (ToM). These deficits have a greater impact than symptoms on occupational and social functioning. Therefore, social cognition represents an important therapeutic target in people with schizophrenia. Recent meta-analyses showed that social cognition training (SCT) is effective in improving social cognition in subjects with schizophrenia; however, real-life functioning is not always ameliorated. Integration of SCT with an intervention targeting metacognitive abilities might improve the integration of social cognitive skills to daily life functioning. Our research group has implemented a new individualized rehabilitation program: the Social Cognition Individualized Activities Lab, SoCIAL, which integrates SCT with a module for narrative enhancement, an intervention targeting metacognitive abilities. The present multi-center randomized controlled study will compare the efficacy of SoCIAL and treatment as usual (TAU) in subjects diagnosed with a schizophrenia-spectrum disorder. The primary outcome will be the improvement of social cognition and real-life functioning; while the secondary outcome will be the improvement of symptoms, functional capacity and neurocognition. The results of this study will add empirical evidence to the benefits and feasibility of SCT and narrative enhancement in people with schizophrenia-spectrum disorders.

Gender Differences in Misdiagnosis and Delayed Diagnosis among Adults with Autism Spectrum Disorder with No Language or Intellectual Disability.

Autism Spectrum Disorder (ASD) is often unrecognized, especially in mild forms and in women. Studies evaluating features associated with missed/misdiagnosis in men and women with ASD are warranted. 61 subjects (22 females, 39 males, age 28.5 ± 10.8 years) with ASD with no language/intellectual deficit were enrolled in the service for the treatment of psychiatric comorbidities in adults with ASD of the ASST Fatebenefratelli-Sacco in Milan (Italy). A detailed clinical history was gathered, and two self-report questionnaires (Autism Spectrum Quotient-AQ and Adult Autism Subthreshold Spectrum-AdAS Spectrum) were administered. 75.4% received their ASD diagnosis average eight years later than the first evaluation by mental health services. Compared to males, females showed a significantly greater delay in referral to mental health services and a significantly higher age at diagnosis of ASD. Among men, diagnostic delay inversely correlated with scores on the AdAS Spectrum total, Verbal communication, Empathy and Inflexibility and adherence to routine domains. Among women, diagnostic delay positively correlated with the Attention to detail score while the age at diagnosis of ASD positively correlated with the AdAS Spectrum Verbal communication and Restricted interests and rumination domain scores. Females were less likely to be correctly diagnosed and more likely to be misdiagnosed at first evaluation than men. Females reported significantly higher scores than men in the Hyper/Hyporeactivity to sensory input domain only among subjects who were misdiagnosed. Our findings provide gender-specific information about ASD patients seeking help for comorbid conditions and might be a primary ground for future research.

Sleep quality among adults with attention deficit hyperactivity disorder or autism spectrum disorder: which is the role of gender and chronotype?

Both Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) present increased prevalence rates of sleep difficulties, which persist into adulthood. However, it is still unclear whether in adults these disorders show specific sleep patterns and which role is played by comorbidities, circadian preferences and gender. This study aimed to describe and compare subjective measures of sleep in adults with ADHD and high-functioning ASD, in relation to the levels of anxiety and depression, chronotype and gender. In a sample of 136 adults (43 ADHD, 43 high-functioning ASD, 50 controls) subjective sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI), and clinical scales were used to assess chronotype and the levels of anxiety and depression. The three groups showed a significant difference in the distribution of chronotypes, with greater prevalence of an Evening chronotype among ASD compared to controls. The MANCOVA using PSQI subscale scores as dependent variables and MEQ-SA score and depression range as covariates showed that the three groups significantly differ in quality, latency, efficiency, and dysfunction scores with a significant differences between ASD and ADHD in efficiency and dysfunction. Compared to men, women showed higher scores on PSQI total and quality subscale across the three groups and higher duration scores only within ASD group. Our results indicate that both ADHD and ASD adults show unique sleep disturbances and suggest that ASD patients, especially women, may display more pronounced disordered sleep.

Insulin resistance is associated with verbal memory impairment in bipolar disorders.

BACKGROUND: Cognitive impairment contributes to deterioration in social, family and work functioning in Bipolar Disorder (BD). Cognitive deficits are present not only during, but also outside of mood episodes. Insulin resistance (IR) impairs cognitive functioning and is frequent in participants with BD. Thus, we hypothesized that IR might contribute to cognitive deficits in remitted BD participants. METHODS: We acquired biochemical (fasting insulin, glucose, lipids) cognitive (California Verbal Learning Test, Digit Span) measures from 100 euthymic participants with BD type I or II. IR was diagnosed using HOMA-IR. RESULTS: BD participants with IR displayed worse composite verbal memory score (-0.38 vs 0.17; F(1, 8.23)=17.90; p = 0.003), while composite working memory scores were comparable in patients with or without IR (-0.20 vs 0.07; F(1, 6.05)=1.64; p = 0.25). Insulin resistance remained significantly associated with composite verbal memory scores (F(1, 47.99)=9.82, p = 0.003) even when we controlled for levels of lipids. The association between IR and verbal memory was not confounded by exposure to antipsychotics, which were not associated with worse cognitive performance (F(1, 2.07)=5.95, p = 0.13). LIMITATIONS: The main limitation is the cross-sectional design, which does not allow us to rule out reverse causation. CONCLUSIONS: We demonstrated that among remitted BD participants without diabetes mellitus, IR was significantly associated with verbal memory performance, even when we controlled for other relevant metabolic or treatment variables. These findings raise the possibility that early detection and treatment of IR, which is reversible, could possibly improve cognitive functioning in at least some BD participants.

ADHD in adults: clinical subtypes and associated characteristics.

INTRODUCTION: Attention Deficit Hyperactivity Disorder (ADHD) is an early onset clinical condition characterized by attention difficulties, hyperactivity and impulsivity which can persist across the lifespan, significantly influencing the evolutionary course and facilitating the rise of psychiatric comorbidities. The presence of different ADHD subtypes in adults is a heterogeneity factor to be recognized in order to orient prognosis and treatment, as indicated by studies that described differences in the characterization of different subtypes in relation to both severity and comorbidities. MATERIALS AND METHODS: In the present study we evaluated the socio-demographic and clinical characteristics of a sample of adults with ADHD and the characteristics associated with the different disorder subtypes. We described 60 patients aged between 18 and 65 years (mean age 34.1) with primary diagnosis of ADHD consecutively admitted to the Regional Centre for diagnosis and treatment of ADHD in adults in Milan. RESULTS: We observed high severity of symptoms and low quality of life, in particular in the "life outlook" dimension. The subtypes distribution was the following: 18.3% inattentive subtype, 8.3% hyperactive/impulsive subtype and 70% combined subtype. The hyperactive/impulsive subtype showed a significantly higher frequency in females, while the inattentive subtype was more frequent in males. Patients with the hyperactive/impulsive subtype showed worse quality of life and more frequent anxiety disorders. CONCLUSIONS: Considering the different clinical profiles among various subtypes, these data add relevance to subtypes classification of adult ADHD.

FEF Excitability in Attentional Bias: A TMS-EEG Study.

The role of distinct cortical regions in guiding social orienting needs further investigation. Our aim was to explore the contribution of the frontal eye field (FEF) in early orienting of attention towards stimuli with social value. We used a TMS-EEG approach to investigate event related potentials (ERPs; no-TMS block) and TMS evoked potentials (TEPs; TMS block) during the cueing phase of a modified version of the dot-probe task, comparing competing (face vs. house) and not competing (house vs. house) conditions. Our results revealed an increased amplitude of ERP components in the competing condition, showing greater posterior N170 and fronto-central vertex positive potential (VPP) and an enhanced frontal negative component at 250-270 ms from cue onset. TMS pulses over the FEF induced similar N170 and VPP amplified components. In addition, in the ERPs, a reduced positivity at 400 ms was shown when the face appeared on the left side vs. the right side of space. In contrast, in the TMS blocks, we found lateralized effects on N170 depending on the side of face presentation. The enhanced cortical excitability induced by TMS over the right FEF significantly correlated with the performance on the behavioral task, suggesting a link between the FEF activity during the cueing phase of the dot-probe task and the subsequent behavioral response times to the targets.

Keeping memory for intentions: a cTBS investigation of the frontopolar cortex.

The present study aimed to investigate the role of frontopolar cortex in prospective memory (PM) by means of inhibitory theta-burst stimulation (cTBS). "Experiment 1"-8 volunteers were evaluated after inhibitory cTBS over left Brodmann area (BA) 10, right BA10, and Cz. In the PM procedure, sequences of 4 words each were presented. During the intersequence delay, subjects had to repeat the sequence in the observed order (ongoing task forward) or in the reverse order (backward). At the occurrence of a target word, subjects had to press a key on the keyboard (PM task). Recall and recognition of the target words were also tested. PM accuracy was lower after cTBS over left BA10 compared with Cz (P = 0.012), whereas it was comparable in right BA10 and Cz conditions. No other significant differences between the 3 conditions were found. "Experiment 2"-8 subjects were administered the same experimental PM procedure as above after inhibitory cTBS over left BA46 and Cz. In this case, none of the tested effects were significant. Our findings corroborate the hypothesis that within the prefrontal cortex, the left BA10 is specifically involved in the mediation of processes related to the execution of delayed intentions.

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.

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.

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.

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

Patients affected by Parkinson's 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.

Hyperexcitability of parietal-motor functional connections in the intact left-hemisphere of patients with neglect.

Hemispatial neglect is common after unilateral brain damage, particularly to perisylvian structures in the right-hemisphere (RH). In this disabling syndrome, behaviour and awareness are biased away from the contralesional side of space towards the ipsilesional side. Theoretical accounts of this in terms of hemispheric rivalry have speculated that the intact left-hemisphere (LH) may become hyper-excitable after a RH lesion, due to release of inhibition from the damaged hemisphere. We tested this directly using a novel twin-coil transcranial magnetic stimulation (TMS) approach to measure excitability within the intact LH of neglect patients. This involved applying a conditioning TMS pulse over left posterior parietal cortex (PPC), in order to test its effect on the amplitude of motor evoked potentials (MEPs) produced by a subsequent test pulse over left motor cortex (M1). Twelve RH stroke patients with neglect, an age-matched group of eight RH stroke patients without neglect, and 10 healthy controls were examined. We found that excitability of left PPC-M1 circuits was higher in neglect patients than the other groups, and related to the degree of neglect on clinical cancellation tests. A follow-up found that 1 Hz repetitive TMS over left PPC normalized this over-excitability, and also ameliorated visual neglect on an experimental measure with chimeric objects. Our results provide 'direct' evidence for pathological over-excitability of the LH in the neglect syndrome, as quantified by left PPC influences on left M1, with implications for possible treatment.

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.

Prefrontal and temporo-parietal involvement in taking others' perspective: TMS evidence.

INTRODUCTION: Understanding the mental states of others entails a number of cognitive processes known as Theory of Mind (ToM). Behavioural and functional neuroimaging evidence suggests that prefrontal and temporo-parietal cortices are involved in these abilities. The present study was aimed at investigating the role of the dorsolateral prefrontal cortex and temporo-parietal junction in ToM by using a repetitive transcranial magnetic stimulation (rTMS) paradigm. MATERIAL AND METHODS: Eleven healthy subjects participated in the study. The experimental ToM procedure was constituted by false belief and faux-pas written stories. Subjects were evaluated in baseline condition (Sham) and after 1Hz rTMS over the left/right dorsolateral prefrontal cortex and temporo-parietal junction. A score for accuracy and response times were recorded. RESULTS: As regards false beliefs, rTMS over right prefrontal and temporo-parietal areas significantly interfered with response times (p<0.05$). The application of rTMS over right/left prefrontal and right temporo-parietal cortices also significantly worsened accuracy in the ability to take the others' perspective in faux-pas tasks as compared to Sham (p

Impaired reproduction of second but not millisecond time intervals in Parkinson's disease.

The basal ganglia have been associated with temporal processing in ranges of milliseconds and seconds. However, results from PD patient studies are elusive. Time perception in these patients has been tested with different approaches including repetitive movement tasks (i.e. finger tapping) and cognitive tasks (i.e. time reproduction), and both abnormal and normal performances have been reported for different time intervals. Furthermore, when PD patients were required to learn two target durations in the same session when they were off medication, they overestimated the short duration and underestimated the long duration in the seconds range. This pattern of temporal accuracy was described as a "migration effect" and was interpreted as a dysfunctional representation of memory for time (Malapani, C., Rakitin, B. C., Levy, R., Meck, W. H., Deweer, B., Dubois, B., et al. (1998). Coupled temporal memories in Parkinson's disease: A dopamine-related dysfunction. Journal of Cognitive Neuroscience, 10, 316-331). Here, we controlled the emergence of similar behaviour also during millisecond time processing in PD patients. A time reproduction task was employed in which subjects were required to estimate intervals in millisecond (500ms) and few second (2000ms) ranges. In the first experiment, these intervals were tested in the same session to verify whether the migration effect was present also between time intervals in different millisecond and few second ranges. In a second experiment, they were not intermingled but were tested in two separate sessions to verify whether abnormalities depended on a selective perceptual deficit of the time intervals tested (i.e. millisecond or second ranges). All experiments were performed in both off and on therapy conditions. Our results demonstrated that PD patients showed no deficits in time estimation for time intervals in either the millisecond or few second range when the different time intervals were tested in separate sessions. This negative finding was obtained in both on and off conditions. However, when the different ranges were tested in the same session, we found that PD patients were impaired selectively for time intervals in the seconds range. Our data seem to indicate that time processing in PD patients for time intervals spanning up to 2s is unimpaired and that abnormalities in such temporal scale may emerge only when patients have to deal with different durations, when timing involves further cognitive processes such as memory and attention.

The influence of rTMS over prefrontal and motor areas in a morphological task: grammatical vs. semantic effects.

We investigated the differential role of two frontal regions in the processing of grammatical and semantic knowledge. Given the documented specificity of the prefrontal cortex for the grammatical class of verbs, and of the primary motor cortex for the semantic class of action words, we sought to investigate whether the prefrontal cortex is also sensitive to semantic effects, and whether the motor cortex is also sensitive to grammatical class effects. We used repetitive transcranial magnetic stimulation (rTMS) to suppress the excitability of a portion of left prefontal cortex (first experiment) and of the motor area (second experiment). In the first experiment we found that rTMS applied to the left prefrontal cortex delays the processing of action verbs' retrieval, but is not critical for retrieval of state verbs and state nouns. In the second experiment we found that rTMS applied to the left motor cortex delays the processing of action words, both name and verbs, while it is not critical for the processing of state words. These results support the notion that left prefrontal and motor cortex are involved in the process of action word retrieval. Left prefrontal cortex subserves processing of both grammatical and semantic information, whereas motor cortex contributes to the processing of semantic representation of action words without any involvement in the representation of grammatical categories.

The role of transcranial magnetic stimulation in the study of cerebellar cognitive function.

Transcranial magnetic stimulation (TMS) allows non-invasive stimulation of brain structures. This technique can be used either for stimulating the motor cortex, recording motor evoked potentials from peripheral muscles, or for modulating the excitability of other non-motor areas in order to establish their necessity for a given task. TMS of the cerebellum can give interesting insights on the cerebellar functions. Paired-TMS techniques, delivering stimuli over the cerebellum followed at various interstimulus intervals by stimuli over the motor cortex, allow studying the pattern of connectivity between the cerebellum and the contralateral motor cortex in physiological as well as in pathological conditions. Repetitive TMS, delivering trains of stimuli at different frequencies, allows interfering with the function of cerebellar circuits during the execution of cognitive tasks. This application complements neuropsychological and neuroimaging studies in the study of the cerebellar involvement in a number of cognitive operations, ranging from procedural memory, working memory and learning through observation.

Repetitive TMS of cerebellum interferes with millisecond time processing.

Time processing is important in several cognitive and motor functions, but it is still unclear how the human brain perceives time intervals of different durations. Processing of time in millisecond and second intervals may depend on different neural networks and there is now considerable evidence to suggest that these intervals are possibly measured by independent brain mechanisms. Using repetitive transcranial magnetic stimulation (rTMS), we determined that the cerebellum is essential in explicit temporal processing of millisecond time intervals. In the first experiment, subjects' performance in a time reproduction task of short (400-600 ms) and long (1,600-2,400 ms) intervals, were evaluated immediately after application of inhibitory rTMS trains over the left and right lateral cerebellum (Cb) and the right dorsolateral prefrontal cortex (DLPFC). We found that rTMS over the lateral cerebellum impaired time perception in the short interval (millisecond range) only; for the second range intervals, impaired timing was found selectively for stimulation of the right DLPFC. In the second experiment, we observed that cerebellar involvement in millisecond time processing was evident when the time intervals were encoded but not when they were retrieved from memory. Our results are consistent with the hypothesis that the cerebellum can be considered as an internal timing system, deputed to assess millisecond time intervals.