Publications by authors named "Sonia Bonnì"

45 Publications

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography.

Hum Brain Mapp 2021 Apr 13;42(5):1343-1358. Epub 2021 Jan 13.

Non-Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Santa Lucia Foundation, Rome, Italy.

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics.
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http://dx.doi.org/10.1002/hbm.25297DOI Listing
April 2021

Cerebellar Intermittent Theta-Burst Stimulation Combined with Vestibular Rehabilitation Improves Gait and Balance in Patients with Multiple Sclerosis: a Preliminary Double-Blind Randomized Controlled Trial.

Cerebellum 2020 Dec;19(6):897-901

Santa Lucia Foundation IRCCS, Via Ardeatina, 306, 00179, Rome, Italy.

Difficulties in gait and balance disorders are among the most common mobility limitations in multiple sclerosis (MS), mainly due to a damage of cerebellar circuits. Moreover, the cerebellum plays a critical role in promoting new motor tasks, which is an essential function for neurorehabilitation. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol able to increase cerebellar activity, on gait and balance in a sample of 20 hospitalized participants with MS, undergoing vestibular rehabilitation (VR), an exercise-based program primarily designed to reduce vertigo and dizziness, gaze instability, and/or imbalance and falls in MS. Patients were assigned to receive either c-iTBS or sham iTBS before being treated with VR during 2 weeks. VR consisted of two types of training: gaze stability and postural stability exercises. The primary outcome measure was the change from baseline in the Tinetti Balance and Gait scale (TBG). The secondary outcome measures were changes from baseline in Berg Balance Scale (BBS), Fatigue Severity Scale (FSS), Two Minute Walking Test (2MWT), and Timed 25-ft walk test (T25FW) scales. MS patients treated with c-iTBS-VR showed a significant improvement in the TBG as compared to patients treated with sham iTBS-VR. Moreover, MS patients in the c-iTBS groups showed better performances in the vestibular-ocular reflex exercises. Combined c-iTBS and VR improves gait and balance abilities more than standard VR treatment in MS patients with a high level of disability.
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http://dx.doi.org/10.1007/s12311-020-01166-yDOI Listing
December 2020

Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease: A Randomized Clinical Trial.

JAMA Netw Open 2020 07 1;3(7):e2010372. Epub 2020 Jul 1.

Department of Behavioral and Clinical Neurology, Santa Lucia Foundation Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy.

Importance: Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD).

Objective: To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD.

Design, Setting, And Participants: This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019.

Interventions: A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47).

Main Outcomes And Measures: The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography.

Results: Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group.

Conclusions And Relevance: In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living.

Trial Registration: ClinicalTrials.gov Identifier: NCT03250741.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.10372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364345PMC
July 2020

Effects of Palmitoylethanolamide Combined with Luteoline on Frontal Lobe Functions, High Frequency Oscillations, and GABAergic Transmission in Patients with Frontotemporal Dementia.

J Alzheimers Dis 2020 ;76(4):1297-1308

Santa Lucia Foundation, IRCCS, Rome, Italy.

Background: Frontotemporal dementia (FTD) is a presenile neurodegenerative disease for which there is no effective pharmacological treatment. Recently, a link has been proposed between neuroinflammation and FTD.

Objective: Here, we aim to investigate the effects of palmitoylethanolamide (PEA) combined with luteoline (PEA-LUT), an endocannabinoid with anti-inflammatory and neuroprotective effects, on behavior, cognition, and cortical activity in a sample of FTD patients.

Methods: Seventeen patients with a diagnosis of probable FTD were enrolled. Cognitive and neurophysiological evaluations were performed at baseline and after 4 weeks of PEA-LUT 700 mg×2/day. Cognitive effects were assessed by Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, Frontal Assessment Battery (FAB), Screening for Aphasia in Neurodegeneration, Activities of Daily Living-Instrumental Activities of Daily Living, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating scale. To investigate in vivo neurophysiological effects of PEA-LUT, we used repetitive and paired-pulse transcranial magnetic stimulation (TMS) protocols assessing LTP-like cortical plasticity, short-interval intracortical inhibition, long-interval intracortical inhibition (LICI), and short-latency afferent inhibition. Moreover, we used TMS combined with EEG to evaluate the effects on frontal lobe cortical oscillatory activity.

Results: Treatment with PEA-LUT was associated with an improvement in NPI and FAB scores. Neurophysiological evaluation showed a restoration of LICI, in particular at ISI 100 ms, suggesting a modulation of GABA(B) activity. TMS-EEG showed a remarkable increase of TMS-evoked frontal lobe activity and of high-frequency oscillations in the beta/gamma range.

Conclusion: PEA-LUT could reduce behavioral disturbances and improve frontal lobe functions in FTD patients through the modulation of cortical oscillatory activity and GABA(B)ergic transmission.
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http://dx.doi.org/10.3233/JAD-200426DOI Listing
January 2020

Effects of Cerebellar Theta Burst Stimulation on Contralateral Motor Cortex Excitability in Patients with Alzheimer's Disease.

Brain Topogr 2020 09 20;33(5):613-617. Epub 2020 Jun 20.

Non-invasive Brain Stimulation Unit, Department of Behavioural and Clinical Neurology, Santa Lucia Foundation IRCCS, Via Ardeatina 306, 00179, Rome, Italy.

Although the cerebellum is not among the most renowned brain structures affected in Alzheimer`s disease (AD), recent evidence suggest that it undergoes degenerative changes during the course of the disease. A main neurophysiological feature of AD patients is the remarkable impairment of long term potentiation (LTP)-like cortical plasticity assessed in the primary motor cortex (M1) using theta burst stimulation (TBS) protocols. In healthy conditions, continuous (cTBS) and intermittent TBS (iTBS) of the cerebellum induce respectively long term depression (LTD)-like and LTP-like after effects in the contralateral M1. Here we aimed at examining the effects of cerebellar TBS on contralateral M1 excitability in a sample of 15 AD patients and 12 healthy age matched controls (HS). Motor evoked potentials (MEPs) were obtained in the contralateral M1 before and after cerebellar cTBS and iTBS protocols. As compared to HS, AD patients showed an impairment of LTP-like cortical plasticity mechanisms following cerebellar iTBS. No difference was observed for the cTBS protocol, in which both populations exhibited the expected LTD-like after effect. This study shows that mechanisms of cerebellar-cortical plasticity are impaired in AD. Given its role in high order cognitive functions, new potential therapeutic strategies could be built up in the future to modulate neural activity in the cerebellum in AD.
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http://dx.doi.org/10.1007/s10548-020-00781-6DOI Listing
September 2020

LTP-like cortical plasticity predicts conversion to dementia in patients with memory impairment.

Brain Stimul 2020 Sep - Oct;13(5):1175-1182. Epub 2020 May 30.

Non Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy; Section of Human Physiology, ECampus University, Novedrate, Italy. Electronic address:

Background: New diagnostic criteria consider Alzheimer's disease (AD) as a clinico-biological entity identifiable in vivo on the presence of specific patterns of CSF biomarkers.

Objective: Here we used transcranial magnetic stimulation to investigate the mechanisms of cortical plasticity and sensory-motor integration in patients with hippocampal-type memory impairment admitted for the first time in the memory clinic stratified according to CSF biomarkers profile.

Methods: Seventy-three patients were recruited and divided in three groups according to the new diagnostic criteria: 1) Mild Cognitive Impaired (MCI) patients (n = 21); Prodromal AD (PROAD) patients (n = 24); AD with manifest dementia (ADD) patients (n = 28). At time of recruitment all patients underwent CSF sampling for diagnostic purposes. Repetitive and paired-pulse transcranial magnetic stimulation protocols were performed to investigate LTP-like and LTD-like cortical plasticity, short intracortical inhibition (SICI) and short afferent inhibition (SAI). Patients were the followed up during three years to monitor the clinical progression or the conversion to dementia.

Results: MCI patients showed a moderate but significant impairment of LTP-like cortical plasticity, while ADD and PROAD groups showed a more severe loss of LTP-like cortical plasticity. No differences were observed for LTD-like cortical plasticity, SICI and SAI protocols. Kaplan-Meyer analyses showed that PROAD and MCI patients converting to dementia had weaker LTP-like plasticity at time of first evaluation.

Conclusion: LTP-like cortical plasticity could be a novel biomarker to predict the clinical progression to dementia in patients with memory impairment at prodromal stages of AD identifiable with the new diagnostic criteria based on CSF biomarkers.
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http://dx.doi.org/10.1016/j.brs.2020.05.013DOI Listing
May 2020

Intermittent Cerebellar Theta Burst Stimulation Improves Visuo-motor Learning in Stroke Patients: a Pilot Study.

Cerebellum 2020 Oct;19(5):739-743

Non Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy.

The cerebellum plays a critical role in promoting learning of new motor tasks, which is an essential function for motor recovery. Repetitive transcranial magnetic stimulation (rTMS) of the cerebellum can be used to enhance learning. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol, on visuo-motor learning in a sample of hemiparetic patients due to recent stroke in the territory of the contralateral middle cerebral artery. Eight stroke patients were enrolled for the purposes of the study in the chronic stage of recovery (i.e., at least 6 months after stroke). In two sessions, Patients were randomly assigned to treatment with real or sham c-iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side. c-iTBS was applied immediately before the learning phase of a visuo-motor adaptation task. Real, but not sham, c-iTBS improved visuo-motor learning as revealed by an increased performance in of the learning phase of the visuo-moto adaptation task. Moreover, we also found that real but not sham c-iTBS induced a sustained improvement in the re-adaptation of the recently learned skill (i.e., when patients were re-tested after 30 min). Taken together, these data point to c-iTBS as a potential novel strategy to promote motor learning in patients with stroke.
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http://dx.doi.org/10.1007/s12311-020-01146-2DOI Listing
October 2020

A Case of Right Temporal Lobectomy for Brain Tumor With Selective Semantic Pictorial Disorder.

Cogn Behav Neurol 2020 03;33(1):52-62

CeRiN, CIMeC, University of Trento, Rovereto, Italy.

Disagreement exists regarding representational and connectionist interpretations of semantic knowledge subserved by the right versus left anterior temporal lobes (ATLs). These interpretations predict a different pattern of impairment in patients with a right unilateral ATL lesion. We conducted a neuropsychological study of a selective semantic pictorial defect exhibited by a 57-year-old man who had undergone a right temporal lobectomy due to the presence of a glioblastoma. The patient was given the Thematic and Taxonomic Semantic task, in which individuals must select, within triplets of words or pictures, the best associates of living or nonliving stimuli, related by thematic or taxonomic links, and presented in the verbal or pictorial modality. The selectivity of the defect was documented by a comparison between the results obtained by our patient and those obtained by healthy controls on living items and on pictures with a thematic relation. The selectivity of the defect was confirmed by a within-subject analysis of the results obtained on all of the task's triplets and those obtained on the stimuli representing living entities with a taxonomic relation. The selectivity of this semantic pictorial defect mainly concerning living entities is consistent with the representational account of semantic defects observed in our patient. In the present case report, a right temporal lobectomy resulted in a selective semantic pictorial defect with the qualitative features predicted by the representational account of semantic defects observed after a unilateral ATL lesion.
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http://dx.doi.org/10.1097/WNN.0000000000000220DOI Listing
March 2020

Health-related quality of life (HRQoL) after stroke: Positive relationship between lower extremity and balance recovery.

Top Stroke Rehabil 2020 10 10;27(7):534-540. Epub 2020 Feb 10.

Non Invasive Brain Stimulation Unit (NIBSU), IRCCS Santa Lucia Foundation , Rome, Italy.

: Stroke survivors have poor long-term quality of life (QoL), especially in the dimensions of mobility and daily activities. : We aimed to investigate how clinical variables influence QoL during subacute stroke rehabilitation. : We assessed the evolution of the health-related QoL (HRQoL), the balance skills, the sensory-motor functions, and the ability in the activity of daily living in 25 hospitalized patients (60.6 ± 11.14 years old; 32% female) during a period of 2 months of stroke rehabilitation. We used the Stroke-Specific Quality of Life scale (SSQoL) to assess the HRQoL; the Berg Balance Scale to assess gait and balance functions; the Fugl-Meyer Assessment scale for sensory-motor functions of upper (UE) and lower limb (LE); and the Barthel Index for activity of daily living. All data have been investigated with the repeated-measures analysis of variance before and after normalization. Multiple Regression Analysis (MRA) has been performed on the normalized data and between the normalized data and the demographic characteristics (Gender; Age; Lesion side). : A significant improvement was found in all the assessed scales during the time of observation. MRA shows a positive regression between HRQoL and the motor recovery of LE and between HRQoL and the balance skills in 60 days from the stroke (MR = 0.88; respectively: = 0.004 and = 0.02). : Our result shows that LE motor recovery impacts the QoL more than motor recovery of UE after 60 days of neurorehabilitation. This finding is strengthened by a positive regression between balance skills and QoL.
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http://dx.doi.org/10.1080/10749357.2020.1726070DOI Listing
October 2020

Classification Accuracy of Transcranial Magnetic Stimulation for the Diagnosis of Neurodegenerative Dementias.

Ann Neurol 2020 03 23;87(3):394-404. Epub 2020 Jan 23.

Department of Clinical and Experimental Sciences, Center for Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.

Objective: Transcranial magnetic stimulation (TMS) has been suggested as a reliable, noninvasive, and inexpensive tool for the diagnosis of neurodegenerative dementias. In this study, we assessed the classification performance of TMS parameters in the differential diagnosis of common neurodegenerative disorders, including Alzheimer disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).

Methods: We performed a multicenter study enrolling patients referred to 4 dementia centers in Italy, in accordance with the Standards for Reporting of Diagnostic Accuracy. All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The investigators who performed the index test were masked to the results of the reference test and all other investigations. We trained and tested a random forest classifier using 5-fold cross-validation. The primary outcome measures were the classification accuracy, precision, recall, and F1 score of TMS in differentiating each neurodegenerative disorder.

Results: A total of 694 participants were included, namely 273 patients diagnosed as AD, 67 as DLB, and 207 as FTD, and 147 healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.89 to 0.92), high precision (0.86-0.92), high recall (0.93-0.98), and high F1 scores (0.89-0.95) in differentiating each neurodegenerative disorder.

Interpretation: TMS is a noninvasive procedure that reliably and selectively distinguishes AD, DLB, FTD, and HC, representing a useful additional screening tool to be used in clinical practice. Ann Neurol 2020;87:394-404.
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http://dx.doi.org/10.1002/ana.25677DOI Listing
March 2020

Improving visuo-motor learning with cerebellar theta burst stimulation: Behavioral and neurophysiological evidence.

Neuroimage 2020 03 30;208:116424. Epub 2019 Nov 30.

Non Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy.

The cerebellum is strongly implicated in learning new motor skills. Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation, can be used to influence cerebellar activity. Our aim was to explore the potential of cerebellar TBS in modulating visuo-motor adaptation, a form of motor learning, in young healthy subjects. Cerebellar TBS was applied immediately before the learning phase of a visuo-motor adaptation task (VAT), in two different experiments. Firstly, we evaluated the behavioral effects of continuous (cTBS), intermittent (iTBS) or sham TBS on the learning, re-adaptation and de-adaptation phases of VAT. Subsequently, we investigated the changes induced by iTBS or sham TBS on motor cortical activity related to each phase of VAT, as measured by concomitant TMS/EEG recordings. We found that cerebellar TBS induced a robust bidirectional modulation of the VAT performance. More specifically, cerebellar iTBS accelerated visuo-motor adaptation, by speeding up error reduction in response to a novel perturbation. This gain of function was still maintained when the novel acquired motor plan was tested during a subsequent phase of re-adaptation. On the other hand, cerebellar cTBS induced the opposite effect, slowing the rate of error reduction in both learning and re-adaptation phases. Additionally, TMS/EEG recordings showed that cerebellar iTBS induced specific changes of cortical activity in the interconnected motor networks. The improved performance was accompanied by an increase of TMS-evoked cortical activity and a generalized desynchronization of TMS-evoked cortical oscillations. Taken together, our behavioral and neurophysiological findings provide the first-time multimodal evidence of the potential efficacy of cerebellar TBS in improving motor learning, by promoting successful cerebellar-cortical reorganization.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116424DOI Listing
March 2020

Effect of Cerebellar Stimulation on Gait and Balance Recovery in Patients With Hemiparetic Stroke: A Randomized Clinical Trial.

JAMA Neurol 2019 02;76(2):170-178

Non Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy.

Importance: Gait and balance impairment is associated with poorer functional recovery after stroke. The cerebellum is known to be strongly implicated in the functional reorganization of motor networks in patients with stroke, especially for gait and balance functions.

Objective: To determine whether cerebellar intermittent θ-burst stimulation (CRB-iTBS) can improve balance and gait functions in patients with hemiparesis due to stroke.

Design, Setting, Participants: This randomized, double-blind, sham-controlled phase IIa trial investigated efficacy and safety of a 3-week treatment of CRB-iTBS coupled with physiotherapy in promoting gait and balance recovery in patients with stroke. Thirty-six patients with consecutive ischemic chronic stroke in the territory of the contralateral middle cerebral artery with hemiparesis were recruited from a neuro-rehabilitation hospital. Participants were screened and enrolled from March 2013 to June 2017. Intention-to-treat analysis was performed.

Interventions: Patients were randomly assigned to treatment with CRB-iTBS or sham iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side immediately before physiotherapy daily during 3 weeks.

Main Outcomes And Measures: The primary outcome was the between-group difference in change from baseline in the Berg Balance Scale. Secondary exploratory measures included the between-group difference in change from baseline in Fugl-Meyer Assessment scale, Barthel Index, and locomotion assessment with gait analysis and cortical activity measured by transcranial magnetic stimulation in combination with electroencephalogram.

Results: A total of 34 patients (mean [SD] age, 64 [11.3] years; 13 women [38.2%]) completed the study. Patients treated with CRB-iTBS, but not with sham iTBS, showed an improvement of gait and balance functions, as revealed by a pronounced increase in the mean (SE) Berg Balance Scale score (baseline: 34.5 [3.4]; 3 weeks after treatment: 43.4 [2.6]; 3 weeks after the end of treatment: 47.5 [1.8]; P < .001). No overall treatment-associated differences were noted in the Fugl-Meyer Assessment (mean [SE], baseline: 163.8 [6.8]; 3 weeks after treatment: 171.1 [7.2]; 3 weeks after the end of treatment: 173.5 [6.9]; P > .05) and Barthel Index scores (mean [SE], baseline: 71.1 [4.92]; 3 weeks after treatment: 88.8 [2.1]; 3 weeks after the end of treatment: 92.2 [2.4]; P > .05). Patients treated with CRB-iTBS, but not sham iTBS, showed a reduction of step width at the gait analysis (mean [SE], baseline: 16.8 [4.8] cm; 3 weeks after treatment: 14.3 [6.2] cm; P < .05) and an increase of neural activity over the posterior parietal cortex.

Conclusions And Relevance: Cerebellar intermittent θ-burst stimulation promotes gait and balance recovery in patients with stroke by acting on cerebello-cortical plasticity. These results are important to increase the level of independent walking and reduce the risk of falling.

Trial Registration: ClinicalTrials.gov Identifier: NCT03456362.
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http://dx.doi.org/10.1001/jamaneurol.2018.3639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439971PMC
February 2019

Transcranial magnetic stimulation predicts cognitive decline in patients with Alzheimer's disease.

J Neurol Neurosurg Psychiatry 2018 12 21;89(12):1237-1242. Epub 2018 Jul 21.

Non Invasive Brain Stimulation Unit, Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy

Objective: To determine the ability of transcranial magnetic stimulation (TMS) in detecting synaptic impairment in patients with Alzheimer's disease (AD) and predicting cognitive decline since the early phases of the disease.

Methods: We used TMS-based parameters to evaluate long-term potentiation (LTP)-like cortical plasticity and cholinergic activity as measured by short afferent inhibition (SAI) in 60 newly diagnosed patients with AD and 30 healthy age-matched subjects (HS). Receiver operating characteristic (ROC) curves were used to assess TMS ability in discriminating patients with AD from HS. Regression analyses examined the association between TMS-based parameters and cognitive decline. Multivariable regression model revealed the best parameters able to predict disease progression.

Results: Area under the ROC curve was 0.90 for LTP-like cortical plasticity, indicating an excellent accuracy of this parameter in detecting AD pathology. In contrast, area under the curve was only 0.64 for SAI, indicating a poor diagnostic accuracy. Notably, LTP-like cortical plasticity was a significant predictor of disease progression (p=0.02), while no other neurophysiological, neuropsychological and demographic parameters were associated with cognitive decline. Multivariable analysis then promoted LTP-like cortical plasticity as the best significant predictor of cognitive decline (p=0.01). Finally, LTP-like cortical plasticity was found to be strongly associated with the probability of rapid cognitive decline (delta Mini-Mental State Examination score ≤-4 points at 18 months) (p=0.04); patients with AD with lower LTP-like cortical plasticity values showed faster disease progression.

Conclusions: TMS-based assessment of LTP-like cortical plasticity could be a viable biomarker to assess synaptic impairment and predict subsequent cognitive decline progression in patients with ADs.
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http://dx.doi.org/10.1136/jnnp-2017-317879DOI Listing
December 2018

Impaired Spike Timing Dependent Cortico-Cortical Plasticity in Alzheimer's Disease Patients.

J Alzheimers Dis 2018 ;66(3):983-991

Department of Behavioural and Clinical Neurology, Non-invasive Brain Stimulation Unit, Santa Lucia Foundation IRCCS, Rome, Italy.

Background: Mechanisms of cortical plasticity have been recently investigated in Alzheimer's disease (AD) patients with transcranial magnetic stimulation protocols showing a clear impairment of long-term potentiation (LTP) cortical-like plasticity mechanisms.

Objective: We aimed to investigate mechanisms of cortico-cortical spike-timing dependent plasticity (STDP) in AD patients investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1).

Methods: We used a cortico-cortical paired associative stimulation (cc-PAS) protocol to repeatedly activate the connection between PPC and M1 of the left-dominant hemisphere in a sample of fifteen AD patients and ten age-matched healthy subjects. PPC transcranial magnetic stimulation preceded (ccPAS +5) or followed M1 stimulation (ccPAS - 5) by 5 ms. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity.

Results: In healthy subjects, ccPAS - 5 protocol induced the expected long-lasting increase of MEP amplitude compatible with LTP-like cortical plasticity while PAS +5 protocol induced the opposite effect. AD patients did not show any significant modification of the amplitude of MEP after both ccPAS protocols.

Conclusions: Our study shows that in AD patients the time-locked activation of human cortico-cortical connections is not able to form STDP, reflecting an impairment of a multi-factor plasticity process.
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http://dx.doi.org/10.3233/JAD-180503DOI Listing
November 2019

LTP-like cortical plasticity is associated with verbal memory impairment in Alzheimer's disease patients.

Brain Stimul 2019 Jan - Feb;12(1):148-151. Epub 2018 Oct 19.

Non Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy; Stroke Unit, Tor Vergata Policlinic, Rome, Italy. Electronic address:

Background: Alzheimer's disease (AD) is characterized by a primary impairment of long-term declarative memory caused by deposition of misfolded protein aggregates. Experimental studies showed that AD neuropathological alterations impair synaptic plasticity and memory performance. Transcranial Magnetic Stimulation protocols have been recently introduced to investigate altered mechanisms of cortical plasticity in AD patients.

Aim: To investigate relationship between Long-Term Potentiation (LTP)-like cortical plasticity and patients' neuropsychological performance.

Methods: We applied intermittent theta burst stimulation and extensive neuropshycological battery in 75 newly diagnosed AD patients.

Results: We found that LTP-like cortical plasticity impairment is selectively associated to a less efficient verbal memory (r = 0.45; p = 0.002), but not to other cognitive functions, independently from biomarkers and other demographic and clinical factors.

Conclusion: These findings suggest that LTP-like cortical plasticity may represent a neurophysiological surrogate of memory in AD patients by evaluating the weight of pathological changes responsible for cognitive dysfunction.
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http://dx.doi.org/10.1016/j.brs.2018.10.009DOI Listing
May 2019

Neurophysiological and clinical effects of blindfolded balance training (BBT) in Parkinson's disease patients: a preliminary study.

Eur J Phys Rehabil Med 2019 Apr 9;55(2):176-182. Epub 2018 May 9.

Santa Lucia Foundation, Scientific Institute for Research and Care, Rome, Italy.

Background: Recent evidence supports the hypothesis that rehabilitative strategies based on sensorimotor stimulation in the neurorehabilitation of Parkinson's disease (PD) may be useful to improve gait in PD patients.

Aim: We supposed that sensorimotor stimulation produces modulation of anticipatory postural adjustments (APAs) arising from the supplementary motor area (SMA). We aimed to investigate the clinical and neurophysiological effects of a blindfolded balance training (BBT).

Design: Randomized controlled trial.

Setting: Italian hospital.

Population: Sixteen PD patients.

Methods: The patients were randomized in two groups, one group treated with two-weeks BBT and one group treated with two-weeks of physical therapy (PT). We assessed gait parameters (swing, stance, double stance phase of cycle gait) and neurophysiological measurement (functional connectivity between SMA and motor area M1) before and after treatments.

Results: We found a decrease of stance and double stance phase and increase of swing phase respect to gait cycle, in BBT group compared to PT group, paralleled by a selective modulation in functional connectivity between M1 and SMA for BBT group.

Conclusions: Our findings support that BBT represents a complementary rehabilitative strategy, based on visual deprivation and proprioceptive perturbation in recovery of gait in PD patients, in short time window, likely involving vestibular system and its connections with motor areas.

Clinical Rehabilitation Impact: The use of vestibular system stimulation, involving SMA-M1 circuits, may be useful to improve gait control in PD patients.
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http://dx.doi.org/10.23736/S1973-9087.18.05126-2DOI Listing
April 2019

Dynamic reorganization of TMS-evoked activity in subcortical stroke patients.

Neuroimage 2018 07 7;175:365-378. Epub 2018 Apr 7.

Non-invasive Brain Stimulation Unit, Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy; Stroke Unit, Tor Vergata Hospital, Rome, Italy. Electronic address:

Since early days after stroke, the brain undergoes a complex reorganization to allow compensatory mechanisms that promote functional recovery. However, these mechanisms are still poorly understood and there is urgent need to identify neurophysiological markers of functional recovery after stroke. Here we aimed to track longitudinally the time-course of cortical reorganization by measuring for the first time EEG cortical activity evoked by TMS pulses in patients with subcortical stroke. Thirteen patients in the sub-acute phase of ischemic subcortical stroke with motor symptoms completed the longitudinal study, being evaluated within 20 days and after 40, 60 and 180 days after stroke onset. For each time-point, EEG cortical activity evoked by single TMS pulses was assessed over the motor and parietal cortex of the affected and unaffected hemisphere. We evaluated global TMS-evoked activity and TMS-evoked oscillations in different frequency bands. These measurements were paralleled with clinical and behavioral assessment. We found that motor cortical activity measured by TMS-EEG varied across time in the affected hemisphere. An increase of TMS-evoked activity was evident at 40 days after stroke onset. Moreover, stroke patients showed a significant increase in TMS-evoked alpha oscillations, as highlighted performing analysis in the time-frequency domain. Notably, these changes indicated that crucial mechanisms of cortical reorganization occur in this short-time window. These changes coincided with the clinical improvement. TMS-evoked alpha oscillatory activity recorded at baseline was associated to better functional recovery at 40 and 60 days' follow-up evaluations, suggesting that the power of the alpha rhythm can be considered a good predictor of motor recovery. This study demonstrates that cortical activity increases dynamically in the early phases of recovery after stroke in the affected hemisphere. These findings point to TMS-evoked alpha oscillatory activity as a potential neurophysiological markers of stroke recovery and could be helpful to determine the temporal window in which neuromodulation should be potentially able to drive neuroplasticity in an effective functional direction.
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http://dx.doi.org/10.1016/j.neuroimage.2018.04.011DOI Listing
July 2018

Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease.

Neuroimage 2018 04 19;169:302-311. Epub 2017 Dec 19.

Neuroimaging Laboratory, Santa Lucia Foundation, IRCCS, Rome, 00179, Italy; Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9RR, East Sussex, UK. Electronic address:

Memory loss is one of the first symptoms of typical Alzheimer's disease (AD), for which there are no effective therapies available. The precuneus (PC) has been recently emphasized as a key area for the memory impairment observed in early AD, likely due to disconnection mechanisms within large-scale networks such as the default mode network (DMN). Using a multimodal approach we investigated in a two-week, randomized, sham-controlled, double-blinded trial the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the PC on cognition, as measured by the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite in 14 patients with early AD (7 females). TMS combined with electroencephalography (TMS-EEG) was used to detect changes in brain connectivity. We found that rTMS of the PC induced a selective improvement in episodic memory, but not in other cognitive domains. Analysis of TMS-EEG signal revealed an increase of neural activity in patients' PC, an enhancement of brain oscillations in the beta band and a modification of functional connections between the PC and medial frontal areas within the DMN. Our findings show that high-frequency rTMS of the PC is a promising, non-invasive treatment for memory dysfunction in patients at early stages of AD. This clinical improvement is accompanied by modulation of brain connectivity, consistently with the pathophysiological model of brain disconnection in AD.
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http://dx.doi.org/10.1016/j.neuroimage.2017.12.048DOI Listing
April 2018

CSF tau is associated with impaired cortical plasticity, cognitive decline and astrocyte survival only in APOE4-positive Alzheimer's disease.

Sci Rep 2017 10 23;7(1):13728. Epub 2017 Oct 23.

Non Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy.

In Alzheimer's disease (AD) patients, apopoliprotein (APOE) polymorphism is the main genetic factor associated with more aggressive clinical course. However, the interaction between cerebrospinal fluid (CSF) tau protein levels and APOE genotype has been scarcely investigated. A possible key mechanism invokes the dysfunction of synaptic plasticity. We investigated how CSF tau interacts with APOE genotype in AD patients. We firstly explored whether CSF tau levels and APOE genotype influence disease progression and long-term potentiation (LTP)-like cortical plasticity as measured by transcranial magnetic stimulation (TMS) in AD patients. Then, we incubated normal human astrocytes (NHAs) with CSF collected from sub-groups of AD patients to determine whether APOE genotype and CSF biomarkers influence astrocytes survival. LTP-like cortical plasticity differed between AD patients with apolipoprotein E4 (APOE4) and apolipoprotein E3 (APOE3) genotype. Higher CSF tau levels were associated with more impaired LTP-like cortical plasticity and faster disease progression in AD patients with APOE4 but not APOE3 genotype. Apoptotic activity was higher when cells were incubated with CSF from AD patients with APOE4 and high tau levels. CSF tau is detrimental on cortical plasticity, disease progression and astrocyte survival only when associated with APOE4 genotype. This is relevant for new therapeutic approaches targeting tau.
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http://dx.doi.org/10.1038/s41598-017-14204-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653826PMC
October 2017

Real-time activation of central cholinergic circuits during recognition memory.

Eur J Neurosci 2017 06 23;45(11):1485-1489. Epub 2017 May 23.

Non-Invasive Brain Stimulation Unit, Neurologia Clinica e Comportamentale, Fondazione Santa Lucia IRCCS, Via Ardeatina 306, 00179, Rome, Italy.

Short latency afferent inhibition (SAI) is a paired-pulse transcranial magnetic stimulation (TMS) protocol that consists in the inhibition of the motor evoked potentials (MEPs) by afferent sensory impulses. SAI is thought to be mediated by cholinergic projections over M1 and can be considered a putative marker of central cholinergic activity. It is known that memory processes are regulated by acetylcholine. Nonetheless, the influence of memory tasks on SAI has not been investigated. Here we tested changes in SAI circuits in healthy subjects performing a computerized non-verbal recognition memory task (RMT) requiring to recognize previously encoded faces. SAI protocol was recorded during five phases of the RMT: baseline, encoding, consolidation, retrieval, and post-task. In the control task, subjects were asked to judge a visual feature of not previously presented faces. SAI protocol was applied over the same conditions as in the RMT. We found that SAI remarkably increases during the retrieval phase of the RMT as compared to baseline. On the other hand no change was observed during the control task. These findings show that SAI can be modulated by ongoing memory processes and support the hypothesis that SAI can be considered as a neurophysiological marker of central cholinergic activity.
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http://dx.doi.org/10.1111/ejn.13588DOI Listing
June 2017

Theta Burst Stimulation of the Precuneus Modulates Resting State Connectivity in the Left Temporal Pole.

Brain Topogr 2017 May 14;30(3):312-319. Epub 2017 Mar 14.

Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179, Rome, Italy.

It has been shown that continuous theta burst stimulation (cTBS) over the precuneus acts on specific memory retrieval abilities. In order to study the neural mechanisms beyond these findings, we combined cTBS and resting-state functional magnetic resonance imaging. Our experimental protocol involved stimulation and sham conditions on a group of healthy subjects, and each condition included a baseline and two follow-up acquisitions (5 and 15 min after baseline) after cTBS. We analysed brain functional connectivity by means of graph theoretical measures, with a specific focus on the network modular structure. Our results showed that cTBS of the precuneus selectively affects the left temporal pole, decreasing its functional connectivity in the first follow-up. Moreover, we observed a significant increase in the size of the module of the precuneus in the second follow-up. Such effects were absent in the sham condition. We observed here a modulation of functional connectivity as a result of inhibitory stimulation over the precuneus. Such a modulation first acts indirectly on the temporal area and then extends the connectivity of the precuneus itself by a feed-back mechanism. Our current findings extend our previous behavioural observations and increase our understanding of the mechanisms underlying the stimulation of the precuneus.
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http://dx.doi.org/10.1007/s10548-017-0559-xDOI Listing
May 2017

Stability and Harmony of Gait in Patients with Subacute Stroke.

J Med Biol Eng 2016 7;36(5):635-643. Epub 2016 Oct 7.

IRCCS Fondazione Santa Lucia, Via Ardeatina 306, 00179 Rome, Italy.

Stroke affects many gait features, such as gait stability, symmetry, and harmony. However, it is still unclear which of these features are directly altered by primary damage, and which are affected by the reduced walking speed. The aim of this study was to analyze the above gait features in patients with subacute stroke with respect to the values observed in age- and speed-matched healthy subjects. A wearable triaxial accelerometer and an optoelectronic device were used for assessing the upright gait stability, symmetry of trunk movements, and harmonic structure of gait phases by means of the root-mean-square (RMS) acceleration of the trunk, harmonic ratio (HR), and gait ratios (GRs), respectively. For healthy subjects, results showed that RMS acceleration increased with speed, HR peaked at a comfortable speed, and GRs tended towards the theoretical value of the golden ratio for speeds >1 m/s. At matched speed conditions, patients showed higher instabilities in the latero-lateral axis ( = 0.001) and reduced symmetry of trunk movements ( = 0.002). Different from healthy subjects, antero-posterior and latero-lateral acceleration harmonics were coupled in patients (R = 0.507,  = 0.023). Conversely, GRs were not more altered in patients than in slow-walking healthy subjects. In conclusion, patients with stroke showed some characteristics similar to those of the elderly when the latter subjects walk slowly, and some altered characteristics, such as increased latero-lateral instabilities coupled with movements performed along the antero-posterior axis.
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http://dx.doi.org/10.1007/s40846-016-0178-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083768PMC
October 2016

Long-term potentiation-like cortical plasticity is disrupted in Alzheimer's disease patients independently from age of onset.

Ann Neurol 2016 08 8;80(2):202-10. Epub 2016 Jul 8.

Non Invasive Brain Stimulation Unit/Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy.

Objective: Alzheimer's disease (AD) is considered an age-related disorder. However, it is unclear whether AD induces the same pathological and neurophysiological modifications in synaptic functions independently from age of disease onset. We used transcranial magnetic stimulation tools to investigate the mechanisms of cortical plasticity and sensory-motor integration in AD patients with a wide range of disease onset.

Methods: We evaluated newly diagnosed sporadic AD (n = 54) in comparison with healthy age-matched controls (HS; n = 24). Cortical plasticity mechanisms of long-term potentiation (LTP) or of long-term depression (LTD) were assessed using respectively intermittent (iTBS) or continuous theta burst stimulation (cTBS) protocols. Sensory-motor integration was evaluated by means of short afferent inhibition (SAI) protocol.

Results: AD patients show after iTBS an impairment of LTP-like cortical plasticity forming a paradoxical LTD in comparison to HS. LTD-like cortical plasticity is similar between AD and HS. LTP-like cortical plasticity is not associated with age, but AD patients presenting with more altered LTP-like cortical plasticity have more-severe cognitive decline at 18 months. SAI is impaired in AD and shows a strong association with the individual age of subjects rather than with disease age of onset.

Interpretation: Cortical LTP disruption is a central mechanism of AD that is independent from age of onset. AD can be described primarily as a disorder of LTP-like cortical plasticity not influenced by physiological aging and associated with a more-severe cognitive decline. Ann Neurol 2016;80:202-210.
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http://dx.doi.org/10.1002/ana.24695DOI Listing
August 2016

Reversal of LTP-Like Cortical Plasticity in Alzheimer's Disease Patients with Tau-Related Faster Clinical Progression.

J Alzheimers Dis 2016 ;50(2):605-16

Stroke Unit, Department of Neuroscience, Tor Vergata Policlinic, Rome, Italy.

Cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ), total tau (t-tau), and phosphorylated tau proteins are associated with different clinical progression in Alzheimer's disease (AD). We enrolled forty newly diagnosed AD patients, who underwent lumbar puncture, and carried out a K-means cluster analysis based on CSF biomarkers levels, resulting in two AD patient groups: Cluster 1 showed relatively high levels of Aβ and low levels of tau; Cluster 2 showed relatively low levels of Aβ and high levels of tau. Cortical plasticity was tested using the intermittent and continuous theta burst stimulation (iTBS and cTBS) protocols evoking respectively long-term potentiation (LTP) and depression (LTD). Cholinergic transmission was tested by the short-latency afferent inhibition protocol. Neurophysiological evaluation showed that the two AD groups differed in terms of cortical plasticity: after iTBS, Cluster 2 patients showed a remarkable reversal of LTP toward LTD that was not observed in Cluster 1. LTD and central cholinergic transmission did not differ between groups. Patients were assessed longitudinally with Mini-Mental State Examination at 6, 12, and 18 month follow-ups. Cluster 2 AD had a faster cognitive decline already evident at the 12 month follow-up. High tau CSF levels were associated with LTD-like cortical plasticity and faster clinical progression. These results suggest that more aggressive tau pathology is associated with prominent LTD-like mechanisms of cortical plasticity and faster cognitive decline.
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http://dx.doi.org/10.3233/JAD-150813DOI Listing
November 2016

TMS evidence for a selective role of the precuneus in source memory retrieval.

Behav Brain Res 2015 Apr 22;282:70-5. Epub 2014 Dec 22.

Non-Invasive Brain Stimulation Unit, Santa Lucia Foundation IRCCS, Rome, Italy; Stroke Unit, Policlinico Tor Vergata, Rome, Italy.

The posteromedial cortex including the precuneus (PC) is thought to be involved in episodic memory retrieval. Here we used continuous theta burst stimulation (cTBS) to disentangle the role of the precuneus in the recognition memory process in a sample of healthy subjects. During the encoding phase, subjects were presented with a series of colored pictures. Afterwards, during the retrieval phase, all previously presented items and a sample of new pictures were presented in black, and subjects were asked to indicate whether each item was new or old, and in the latter case to indicate the associated color. cTBS was delivered over PC, posterior parietal cortex (PPC) and vertex before the retrieval phase. The data were analyzed in terms of hits, false alarms, source errors and omissions. cTBS over the precuneus, but not over the PPC or the vertex, induced a selective decrease in source memory errors, indicating an improvement in context retrieval. All the other accuracy measurements were unchanged. These findings suggest a direct implication of the precuneus in successful context-dependent retrieval.
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http://dx.doi.org/10.1016/j.bbr.2014.12.032DOI Listing
April 2015

Processing past tense in the left cerebellum.

Neurocase 2015 6;21(2):185-9. Epub 2014 Feb 6.

a Dipartimento di Psicologia , Università di Palermo , Palermo , Italy.

We report the case of a patient with ischemic lesion of the left cerebellum, who showed specific deficits in processing past versus future tense of action verbs. These findings confirm, in the presence of cerebellar damage, previous results obtained with transcranial magnetic stimulation in healthy subjects and suggest a specificity of the left cerebellum for preparation of responses to the past tense of action verbs. As part of the procedural brain, the cerebellum could play a role in applying the linguistic rules for selection of morphemes typical of past and future tense formation.
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http://dx.doi.org/10.1080/13554794.2013.878730DOI Listing
December 2015

Role of the anterior temporal lobes in semantic representations: Paradoxical results of a cTBS study.

Neuropsychologia 2015 Sep 8;76:163-9. Epub 2014 Nov 8.

Non-invasive Brain Stimulation Unit, Santa Lucia Foundation IRCCS, Rome, Italy; Center for Neuropsychological Research, Institute of Neurology, Catholic University of Rome, Rome, Italy.

According to the 'Semantic Hub' model, which was developed from data gathered in the moderate to advanced stages of semantic dementia (SD), a unitary amodal mechanism, located in the anterior parts of both temporal lobes (ATLs), should support the interactive activation of semantic representations in all modalities and for all semantic categories. This model has been challenged by clinical findings, which show that in the early stages of SD, when important asymmetries can be observed at the level of the right and left ATLs, the semantic impairment can be modality-specific, mainly affecting lexical-semantic knowledge when the left temporal lobe is more atrophic and pictorial representations when atrophy prevails on the right side. On the other hand, findings of experiments conducted in normal subjects with repetitive transcranial magnetic stimulations (rTMS), support the unitary model. In the most compelling of these studies, rTMS was used to investigate the role of right and left ATLs directly, by comparing semantic processing of the same concepts, presented as written words or pictures. The efficiency of semantic processing for words and pictures was reduced to the same degree by rTMS applied to the left and right ATLs. However, to consider more in depth some methodological inconsistencies of these studies and with the aim of discussing the effects of rTMS on high-level cognitive functions, we decided to repeat that experimental paradigm, using the continuous theta burst stimulation (cTBS) protocol over the right ATL, left ATL and vertex (as control site). A significant interaction was found between side of cTBS application and type of stimulus, but, contrary to our predictions, we observed significantly faster (rather than slower) responses to pictures after application of cTBS to the right ATL and no difference between responses to written words after application of cTBS to the left ATL in comparison with the vertex. These unexpected results are discussed with respect to the nature of the semantic representations supported by the right and left ATLs and to re-appraisal of the 'virtual lesion' account to explain results obtained with rTMS experiments on high-level cognitive functions.
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http://dx.doi.org/10.1016/j.neuropsychologia.2014.11.002DOI Listing
September 2015

Cingulate neglect in humans: disruption of contralesional reward learning in right brain damage.

Cortex 2015 Jan 27;62:73-88. Epub 2014 Aug 27.

Fondazione Santa Lucia IRCCS, Roma, Italy; Dipartimento di Psicologia 39, Università degli Studi di Roma 'La Sapienza', Roma, Italy. Electronic address:

Motivational valence plays a key role in orienting spatial attention. Nonetheless, clinical documentation and understanding of motivationally based deficits of spatial orienting in the human is limited. Here in a series of one group-study and two single-case studies, we have examined right brain damaged patients (RBD) with and without left spatial neglect in a spatial reward-learning task, in which the motivational valence of the left contralesional and the right ipsilesional space was contrasted. In each trial two visual boxes were presented, one to the left and one to the right of central fixation. In one session monetary rewards were released more frequently in the box on the left side (75% of trials) whereas in another session they were released more frequently on the right side. In each trial patients were required to: 1) point to each one of the two boxes; 2) choose one of the boxes for obtaining monetary reward; 3) report explicitly the position of reward and whether this position matched or not the original choice. Despite defective spontaneous allocation of attention toward the contralesional space, RBD patients with left spatial neglect showed preserved contralesional reward learning, i.e., comparable to ipsilesional learning and to reward learning displayed by patients without neglect. A notable exception in the group of neglect patients was L.R., who showed no sign of contralesional reward learning in a series of 120 consecutive trials despite being able of reaching learning criterion in only 20 trials in the ipsilesional space. L.R. suffered a cortical-subcortical brain damage affecting the anterior components of the parietal-frontal attentional network and, compared with all other neglect and non-neglect patients, had additional lesion involvement of the medial anterior cingulate cortex (ACC) and of the adjacent sectors of the corpus callosum. In contrast to his lateralized motivational learning deficit, L.R. had no lateral bias in the early phases of attentional processing as he suffered no contralesional visual or auditory extinction on double simultaneous tachistoscopic and dichotic stimulation and detected, with no exception, single contralesional visual and auditory stimuli. In a separate study, we were able to compare L.R. with another RBD patient, G.P., who had a selective lesion in the right ACC, in the adjacent callosal connections and the medial-basal prefrontal cortex. G.P. had no contralesional neglect and displayed normal reward learning both in the left and right side of space. These findings show that contralesional reward learning is generally preserved in RBD patients with left spatial neglect and that this can be exploited in rehabilitation protocols. Contralesional reward learning is severely disrupted in neglect patients when an additional lesion of the ACC is present: however, as demonstrated by the comparison between L.R. and G.P. cases, selective unilateral lesion of the right ACC does not produce motivational neglect for the contralesional space.
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http://dx.doi.org/10.1016/j.cortex.2014.08.008DOI Listing
January 2015

Selective deficit of spatial short-term memory: Role of storage and rehearsal mechanisms.

Cortex 2014 Oct 11;59:22-32. Epub 2014 Jul 11.

IRCCS Fondazione Santa Lucia, Rome, Italy; Clinica Neurologica, Tor Vergata University, Rome, Italy.

We report the neuropsychological and MRI investigation of a patient (GP) who developed a selective impairment of spatial short-term memory (STM) following damage to the dorso-mesial areas of the right frontal lobe. We assessed in this patient spatial STM with an experimental procedure that evaluated immediate and 5-20 s delayed recall of verbal, visual and spatial stimuli. The patient scored significantly worse than normal controls on tests that required delayed recall of spatial data. This could not be ascribed to a deficit of spatial episodic long-term memory because amnesic patients performed normally on these tests. Conversely, the patient scored in the normal range on tests of immediate recall of verbal, visual and spatial data and tests of delayed recall of verbal and visual data. Comparison with a previously described patient who had a selective deficit in immediate spatial recall and an ischemic lesion that affected frontal and parietal dorso-mesial areas in the right hemisphere (Carlesimo GA, Perri R, Turriziani P, Tomaiuolo F, Caltagirone C. Remembering what but not where: independence of spatial and visual working memory in the human brain. Cortex. 2001 Sep; 37(4):519-34) suggests that the right parietal areas are involved in the short-term storage of spatial information and that the dorso-mesial regions of the right frontal underlie mechanisms for the delayed maintenance of the same data.
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http://dx.doi.org/10.1016/j.cortex.2014.06.004DOI Listing
October 2014

Cerebellar theta burst stimulation in stroke patients with ataxia.

Funct Neurol 2014 Jan-Mar;29(1):41-5

Evidence for effective improvement of the symptoms of cerebellar stroke is still limited. Here, we investigated the effects of repetitive transcranial magnetic stimulation (rTMS) applied over the injured cerebellar hemisphere in six patients with posterior circulation stroke. We applied a two-week course of cerebellar intermittent theta burst stimulation (iTBS). Before and after the iTBS treatment, paired-pulse TMS methods were used to explore: i) the functional connectivity between the cerebellar hemisphere and the contralateral primary motor cortex (M1), by means of the cerebellar brain inhibition (CBI) protocol; and ii) the intracortical circuits in the contralateral M1, by means of the short intra-cortical inhibition (SICI) and intra-cortical facilitation (ICF) protocols. Patients were also evaluated using the Modified International Cooperative Ataxia Rating Scale (MICARS). Cerebellar iTBS induced a decrease in CBI and an increase in ICF at an interstimulus interval of 15 msec. These neurophysiological changes were paralleled by a clinical improvement, shown by the MICARS posture and gait subscale scores. Cerebellar iTBS could be a promising tool to promote recovery of cerebellar stroke patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172246PMC
February 2015