Publications by authors named "Raffaele Nardone"

240 Publications

Effects of Intermittent Theta Burst Stimulation on the Clock Drawing Test Performances in Patients with Alzheimer's Disease.

Brain Topogr 2021 Apr 8. Epub 2021 Apr 8.

Department of Neurology, Christian Doppler Clinic, Paracelsus Medical University, Salzburg, Austria.

The clock drawing test (CDT) is widely used in clinical neuropsychological practice. However, its neuroanatomical correlates have not been well established. This study investigated the effects of theta burst stimulation (TBS) applied over different brain regions on CDT scores in patients with Alzheimer's disease (AD). The 10-20 positions F3, F4, T3, T4, TP3, TP4, P3, P4, as determined by a 10-20 positioning cap, were targeted. Excitatory intermittent TBS (iTBS) was given over the above-mentioned eight regions to ten AD patients and ten control subjects on separate days. CDT was administered at baseline (T0), during the 5 min following the TBS (T1) and 60 min after TBS (T2), with an inter-session interval of at least 4 days. iTBS over TP4 and P4 transiently increased Rouleau CDT score in AD patients. When targeting TP4 and P4, mainly the area of the supramarginal/angular gyrus and the inferior parietal lobe, corresponding respectively to the Brodmann areas 40/39 and 7/40, are reached. iTBS thus seems able to modulate activity of the right posterior parietal cortex in AD patients performing the CDT. Our results provide physiological evidence that those parietal regions are functionally important for the execution of the Rouleau CDT. This finding suggests that CDT has reliable neuroanatomical correlates, and support the notion that this test can be used as a good marker of right parietal brain dysfunction. The present study also highlights the therapeutic potential of the induction of neuromodulatory effects using non-invasive brain stimulation techniques.
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http://dx.doi.org/10.1007/s10548-021-00836-2DOI Listing
April 2021

TMS-EEG Co-Registration in Patients with Mild Cognitive Impairment, Alzheimer's Disease and Other Dementias: A Systematic Review.

Brain Sci 2021 Feb 27;11(3). Epub 2021 Feb 27.

Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, 5020 Salzburg, Austria.

An established method to assess effective brain connectivity is the combined use of transcranial magnetic stimulation with simultaneous electroencephalography (TMS-EEG) because TMS-induced cortical responses propagate to distant anatomically connected brain areas. Alzheimer's disease (AD) and other dementias are associated with changes in brain networks and connectivity, but the underlying pathophysiology of these processes is poorly defined. We performed here a systematic review of the studies employing TMS-EEG co-registration in patients with dementias. TMS-EEG studies targeting the motor cortex have revealed a significantly reduced TMS-evoked P30 in AD patients in the temporo-parietal cortex ipsilateral to stimulation side as well as in the contralateral fronto-central area, and we have demonstrated a deep rearrangement of the sensorimotor system even in mild AD patients. TMS-EEG studies targeting other cortical areas showed alterations of effective dorsolateral prefrontal cortex connectivity as well as an inverse correlation between prefrontal-to-parietal connectivity and cognitive impairment. Moreover, TMS-EEG analysis showed a selective increase in precuneus neural activity. TMS-EEG co-registrations can also been used to investigate whether different drugs may affect cognitive functions in patients with dementias.
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http://dx.doi.org/10.3390/brainsci11030303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997266PMC
February 2021

Stroke management during the coronavirus disease 2019 (COVID-19) pandemic: experience from three regions of the north east of Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige).

Neurol Sci 2021 Mar 4. Epub 2021 Mar 4.

Stroke Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Background: Efficiency of care chain response and hospital reactivity were and are challenged for stroke acute care management during the pandemic period of coronavirus disease 2019 (COVID-19) in North-Eastern Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige), counting 7,193,880 inhabitants (ISTAT), with consequences in acute treatment for patients with ischemic stroke.

Methods: We conducted a retrospective data collection of patients admitted to stroke units eventually treated with thrombolysis and thrombectomy, ranging from January to May 2020 from the beginning to the end of the main first pandemic period of COVID-19 in Italy. The primary endpoint was the number of patients arriving to these stroke units, and secondary endpoints were the number of thrombolysis and/or thrombectomy. Chi-square analysis was used on all patients; furthermore, patients were divided into two cohorts (pre-lockdown and lockdown periods) and the Kruskal-Wallis test was used to test differences on admission and reperfusive therapies.

Results: In total, 2536 patients were included in 22 centers. There was a significant decrease of admissions in April compared to January. Furthermore, we observed a significant decrease of thrombectomy during the lockdown period, while thrombolysis rate was unaffected in the same interval across all centers.

Conclusions: Our study confirmed a decrease in admission rate of stroke patients in a large area of northern Italy during the lockdown period, especially during the first dramatic phase. Overall, there was no decrease in thrombolysis rate, confirming an effect of emergency care system for stroke patients. Instead, the significant decrease in thrombectomy rate during lockdown addresses some considerations of local and regional stroke networks during COVID-19 pandemic evolution.
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http://dx.doi.org/10.1007/s10072-021-05066-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930104PMC
March 2021

Connectivity Analysis during Rubber Hand Illusion-A Pilot TMS-EEG Study in a Patient with SCI.

Neural Plast 2021 8;2021:6695530. Epub 2021 Feb 8.

Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience, Austria.

Background: Bodily self-perception is an important concept for several neurological disorders, including spinal cord injury (SCI). Changing one's bodily self-perception, e.g., via rubber hand illusion (RHI), induces alterations of bottom-up and top-down pathways and with this the connectivity between involved brain areas. We aim to examine whether (1) this process can be manipulated by changing cortical excitability, (2) connectivity between relevant brain areas differ when the RHI cannot be evoked, and (3) how this projection differs in a patient with SCI.

Method: We applied RHI and facilitatory theta burst stimulation (TBS) on the right primary somatosensory cortex (S1) of 18 healthy participants and one patient with incomplete, cervical SCI. During RHI, we recorded high-density electroencephalography (HD-EEG) and extracted directed and nondirected connectivity measures.

Results: There is no difference in connectivity between sham and real TBS or in the effectivity of RHI. We observed a higher laterality in the patient, i.e., higher connectivity of the right and lower of the left hemisphere. Besides this, connectivity patterns do not differ between healthy participants and the patient.

Conclusion: This connectivity pattern might represent a neuroplastic response in the attempt to overcome the functional impairment of the patient resulting in a similar overall connectivity pattern to the healthy participants, yet with a higher sensitivity towards RHI and a higher laterality. The cortico-cortical communication was not altered depending on whether the illusion was provoked or not; hence, the perceptory illusion could not be observed in the EEG analysis.
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http://dx.doi.org/10.1155/2021/6695530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884106PMC
February 2021

The Babinski sign in the first Italian reports.

Neurol Sci 2021 Jan 26. Epub 2021 Jan 26.

Department of Neurology, Hospital of Merano (SABES-ASDAA), Via Rossini, 5, 39012, Merano, BZ, Italy.

The Babinski sign, named after Joseph François Félix Babiński (1857-1932), is one of the most important in clinical neurology. It refers to the upward movement of the great toe following stimulation of the foot sole and is associated with a dysfunction of the pyramidal tract. The BS was recognized and adopted by neurologists all over the world immediately after its first description. In 1899, this sign was first introduced to the Italian scientific community at two different medical meetings. Some opinions on its clinical value and underlying pathophysiology were discordant, possibly reflecting suboptimal diagnostic accuracy of the first observations. Giovanni Mingazzini (1859-1929) first suggested that the BS reflects a complex mechanism emerging in patients with pyramidal tract dysfunction, whereas Giovanni Boeri (1867-1946) emphasized that the BS can be elicited if the neuromuscular structures underlying it are intact. Although some of their opinions eventually proved wrong, early Italian neurologists further contributed to the advancement in the understanding of this phenomenon.
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http://dx.doi.org/10.1007/s10072-021-05081-wDOI Listing
January 2021

Classification accuracy of TMS for the diagnosis of mild cognitive impairment.

Brain Stimul 2021 Mar-Apr;14(2):241-249. Epub 2021 Jan 13.

Neurology Unit, Department of Clinial and Experimental Sciences, University of Brescia, Italy. Electronic address:

Objective: To evaluate the performance of a Random Forest (RF) classifier on Transcranial Magnetic Stimulation (TMS) measures in patients with Mild Cognitive Impairment (MCI).

Methods: We applied a RF classifier on TMS measures obtained from a multicenter cohort of patients with MCI, including MCI-Alzheimer's Disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), and healthy controls (HC). All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The primary outcome measures were the classification accuracy, precision, recall and F1-score of TMS in differentiating each disorder.

Results: 160 participants were included, namely 64 patients diagnosed as MCI-AD, 28 as MCI-FTD, 14 as MCI-DLB, and 47 as healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.72 to 0.86), high precision (0.72-0.90), high recall (0.75-0.98), and high F1-scores (0.78-0.92), in differentiating each neurodegenerative disorder. By computing a new classifier, trained and validated on the current cohort of MCI patients, classification indices showed even higher accuracy (ranging from 0.83 to 0.93), precision (0.87-0.89), recall (0.83-1.00), and F1-scores (0.85-0.94).

Conclusions: TMS may be considered a useful additional screening tool to be used in clinical practice in the prodromal stages of neurodegenerative dementias.
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http://dx.doi.org/10.1016/j.brs.2021.01.004DOI Listing
January 2021

The Ties That Bind: Aberrant Plasticity and Networks Dysfunction in Movement Disorders-Implications for Rehabilitation.

Brain Connect 2021 Feb 9. Epub 2021 Feb 9.

Department of Neurorehabilitation, Hospital of Vipiteno (SABES-ASDAA), Vipiteno-Sterzing, Italy.

Movement disorders encompass various conditions affecting the nervous system. The pathological processes underlying movement disorders lead to aberrant synaptic plastic changes, which in turn alter the functioning of large-scale brain networks. Therefore, clinical phenomenology does not only entail motor symptoms but also cognitive and motivational disturbances. The result is the disruption of motor learning and motor behavior. Due to this complexity, the responsiveness to standard therapies could be disappointing. Specific forms of rehabilitation entailing goal-based practice, aerobic training, and the use of noninvasive brain stimulation techniques could "restore" neuroplasticity at motor-cognitive circuitries, leading to clinical gains. This is probably associated with modulations occurring at both molecular (synaptic) and circuitry levels (networks). Several gaps remain in our understanding of the relationships among plasticity and neural networks and how neurorehabilitation could promote clinical gains is still unclear. In this review, we outline first the networks involved in motor learning and behavior and analyze which mechanisms link the pathological synaptic plastic changes with these networks' disruption in movement disorders. Therefore, we provide theoretical and practical bases to be applied for treatment in rehabilitation.
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http://dx.doi.org/10.1089/brain.2020.0971DOI Listing
February 2021

Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: Insights into a challenging symptom.

J Neurol Sci 2021 01 14;420:117271. Epub 2020 Dec 14.

Department of Neurorehabilitation, Hospital of Vipiteno (SABES-ASDAA), Vipiteno-Sterzing, Italy.

More than half of patients who recover from COVID-19 experience fatigue. We studied fatigue using neuropsychological and neurophysiological investigations in post-COVID-19 patients and healthy subjects. Neuropsychological assessment included: Fatigue Severity Scale (FSS), Fatigue Rating Scale, Beck Depression Inventory, Apathy Evaluation Scale, cognitive tests, and computerized tasks. Neurophysiological examination was assessed before (PRE) and 2 min after (POST) a 1-min fatiguing isometric pinching task and included: maximum compound muscle action potential (CMAP) amplitude in first dorsal interosseous muscle (FDI) following ulnar nerve stimulation, resting motor threshold, motor evoked potential (MEP) amplitude and silent period (SP) duration in right FDI following transcranial magnetic stimulation of the left motor cortex. Maximum pinch strength was measured. Perceived exertion was assessed with the Borg-Category-Ratio scale. Patients manifested fatigue, apathy, executive deficits, impaired cognitive control, and reduction in global cognition. Perceived exertion was higher in patients. CMAP and MEP were smaller in patients both PRE and POST. CMAP did not change in either group from PRE to POST, while MEP amplitudes declined in controls POST. SP duration did not differ between groups PRE, increased in controls but decreased in patients POST. Patients' change of SP duration from PRE to POST was negatively correlated to FSS. Abnormal SP shortening and lack of MEP depression concur with a reduction in post-exhaustion corticomotor inhibition, suggesting a possible GABA-ergic dysfunction. This impairment might be related to the neuropsychological alterations. COVID-19-associated inflammation might lead to GABAergic impairment, possibly representing the basis of fatigue and explaining apathy and executive deficits.
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http://dx.doi.org/10.1016/j.jns.2020.117271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834526PMC
January 2021

Posterior reversible encephalopathy syndrome: role of transorbital ultrasound.

Neurol Sci 2021 03 22;42(3):1171-1174. Epub 2020 Sep 22.

Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.

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http://dx.doi.org/10.1007/s10072-020-04719-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870592PMC
March 2021

Statins in primary prevention of poststroke seizures and epilepsy: A systematic review.

Epilepsy Behav 2020 11 8;112:107400. Epub 2020 Sep 8.

Department of Neurology, Hospital of Merano (SABES-ASDAA), Merano-Meran, Italy. Electronic address:

Introduction: Cerebrovascular disease is the most common cause of seizures in adults and the elderly. So far, no drug is recommended as primary prevention of acute symptomatic poststroke seizures (ASPSS) or poststroke epilepsy (PSE). This systematic review aimed to evaluate the association between the use of statins after stroke and the risk of developing ASPSS or PSE following cerebral infarct or hemorrhage (primary prevention).

Methods: We included studies evaluating the poststroke use of statins as primary prevention of ASPSS or PSE, irrespective of stroke type. We excluded uncontrolled studies and studies with prestroke statin use. The main outcome included the occurrence of ASPSS or PSE and the effect of statins by type and dose. The odds ratios (ORs) or hazard ratios (HR) with 95% confidence intervals (CIs) were used as the measures of association between treatment and outcome.

Results: Four studies were included. One study showed a reduced risk of ASPSS after ischemic stroke (OR: 0.25; 95% CI: 0.10-0.59; p = 0.0016). Three studies consistently reported a reduced risk of PSE after ischemic stroke, and one study a reduced risk of PSE after hemorrhagic stroke (HR: 0.62; 95% CI: 0.42-0.90; p = 0.01).

Conclusions: Data from the literature suggest an association between statin use and a reduced risk of ASPSS after ischemic stroke and a reduced risk of PSE after ischemic and hemorrhagic stroke. Although the certainty of the evidence is low, these findings appear promising and worthy of further investigation.
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http://dx.doi.org/10.1016/j.yebeh.2020.107400DOI Listing
November 2020

"Spreading the word of the master": the contribution of Italian physicians in the early dissemination of Jean-Martin Charcot's theories.

Neurol Sci 2020 Dec 25;41(12):3787-3794. Epub 2020 Jul 25.

, Brou, France.

Jean-Martin Charcot (1825-1893) laid the foundations of modern neurology. The lectures he gave at La Salpêtrière Hospital in Paris attracted a large number of visitors from all over the world. Some of them transcribed these clinical lessons, translating and publishing them when returning home. This article discusses the contribution of some Italian physicians (Gaetano Rummo, 1853-1917; Domenico Miliotti; Giulio Melotti, 1857-19?; and Augusto Tebaldi, 1833-1895), who were pioneers in disseminating the ideas and discoveries of Charcot. The early Italian translations were based on personal handwritten notes and memories, not relying on official French versions personally revised or edited by Charcot himself. As such, their veracity cannot always be verified, particularly in the lack of other independent works reporting details on the same lectures. However, the Italian transcriptions providing information which cannot be found elsewhere in Charcot's corpus of works represent an invaluable and a unique source for fully understanding some theories by the French neurologist. Furthermore, they are the first documents providing original materials related to Charcot's teaching translated in a foreign language. The first Italian publications that included photographs of patients were deeply influenced by and clearly modeled on the famous volumes of the Iconographie photographique de la Salpêtrière and further contributed to the early dissemination of Charcot's theories.
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http://dx.doi.org/10.1007/s10072-020-04606-zDOI Listing
December 2020

Effects of intrathecal baclofen therapy in subjects with disorders of consciousness: a reappraisal.

J Neural Transm (Vienna) 2020 09 24;127(9):1209-1215. Epub 2020 Jul 24.

Department of Neurology, Hospital of Merano (SABES-ASDAA), Merano-Meran, Italy.

Baclofen is a structural analogue of gamma-amino-butyric acid (GABA), which reduces spastic hypertonia of striated muscle due to a mechanism of GABA-ergic inhibition of mono- and polysynaptic reflexes at the spinal level. There are reports of patients with severe disorders of consciousness that presented a substantial improvement following intrathecal baclofen (ITB) administration for severe spasticity. The neural mechanisms underlying the clinical recovery after ITB have not yet been clarified. Baclofen could modulate sleep-wake cycles that may be dysregulated and thus interfere with alertness and awareness. The diminished proprioceptive and nociceptive sensory inputs may relieve thalamo-cortical neural networks involved in maintaining the consciousness of the self and the world. ITB treatment might also promote the recovery of an impaired GABAergic cortical tone, restoring the balance between excitatory and inhibitory cortical activity. Furthermore, glutamatergic synapses are directly or indirectly modulated by GABA-ergic receptors. Neurophysiological techniques (such as transcranial magnetic stimulation, electroencephalography, or the combination of both) can be helpful to explore the effects of intrathecal or oral baclofen on the modulation of neural cortical circuits in humans with disorders of consciousness.
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http://dx.doi.org/10.1007/s00702-020-02233-8DOI Listing
September 2020

Giovanni Mingazzini (1859-1929) and his opposition to Pierre Marie's conception of motor aphasia.

Neurol Sci 2020 Oct 13;41(10):2973-2976. Epub 2020 Jul 13.

Department of Neurology, Franz Tappeiner Hospital, Via Rossini, 5-39012, Merano, BZ, Italy.

This article describes the contribution of Giovanni Mingazzini (1859-1929), the "Father of Italian Neurology," in the description of the subcortical structures involved in motor aphasia and his opposition to Pierre Marie's (1853-1940) conception of aphasia. In one of the most famous controversies in the history of neurology, the French neurologists Joseph Jules Dejerine (1849-1917), Augusta Dejerine-Klumpke (1859-1927), and Pierre Marie (1853-1940) faced each other during the three symposiums of the French Society of Neurology in 1908. The debate, which was later called "the aphasia quarrel", focused on the subject of aphasia. In an article published in January of the same year, the Italian neurologist Giovanni Mingazzini had already explicitly challenged Pierre Marie's conception of aphasia. Mingazzini's contribution to the "aphasia debate" deserves to be remembered for the emphasis on the role of Broca's area, and for his detailed description of a subcortical region representing "the crossroad of the language pathways" which, if lesioned, could cause motor aphasia.
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http://dx.doi.org/10.1007/s10072-020-04568-2DOI Listing
October 2020

Transcranial magnetic stimulation and gait disturbances in Parkinson's disease: A systematic review.

Neurophysiol Clin 2020 Jul 30;50(3):213-225. Epub 2020 Jun 30.

Department of Neurorehabilitation, Hospital of Vipiteno, Vipiteno, Italy; Research Unit for Neurorehabilitation South Tyrol, Bolzano, Italy.

Transcranial magnetic stimulation (TMS) may offer a reliable means of characterizing important pathophysiologic aspects of motor impairments in Parkinson's disease (PD). Moreover, high-frequency repetitive TMS (rTMS), especially if delivered bilaterally over motor cortical regions, can have beneficial effects on parkinsonian motor symptoms. However, only a few studies have investigated the effects of rTMS on freezing of gait (FOG) and other gait disturbances in PD. We aimed at investigating in this narrative review the usefulness of TMS for exploring the pathophysiology of gait impairment and at evaluating the therapeutic effects of rTMS in this context. The combination of rTMS and treadmill training was found to enhance the effect of physical therapy. Use of an H-coil enables stimulation of deep regions of the brain (for example medial prefrontal cortex) and may be used as a target for add-on therapy in the future. In contrast, theta burst stimulation has proven to be ineffective in treating gait disturbances in PD patients. Dual-mode NIBS, in particular preconditioning motor cortex rTMS by transcranial direct current stimulation, might also represent a novel therapeutic approach for patients with gait disturbances. Recent studies suggest that the supplementary motor area could be an appropriate target for brain stimulation when treating PD patients with FOG. Further large sample and well-designed clinical studies are required to evaluate how the possible positive effects of rTMS can be sustained over time and to determine the optimal stimulation protocols including target, stimulation intensity/duration and number of sessions.
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http://dx.doi.org/10.1016/j.neucli.2020.05.002DOI Listing
July 2020

Altered response to repetitive transcranial magnetic stimulation in patients with chronic primary insomnia.

Sleep Med 2020 08 5;72:126-129. Epub 2020 Apr 5.

Department of Psychology, University of Akureyri, Iceland.

Background: We aimed at evaluating the amplitude changes of the motor evoked potentials (MEPs) induced by of low-frequency (LF) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) in10 patients with primary insomnia (PI) and in 10 age-matched healthy controls.

Methods: Median peak-to-peak MEP amplitudes were assessed in all subjects at three times: at baseline (T), after the first train of a single rTMS session (T), and after the whole rTMS procedure (T). This consists of 20 trains of 1 Hz stimulation with 50 stimuli per train and an intertrain interval of 30 s.

Results: Resting motor threshold (RMT) and MEPs amplitude did not differ between the two groups at T. A reduction of MEP size was observed at both T and T in all subjects, but this was significantly less pronounced in patients than in control subjects.

Conclusions: The lack of MEP inhibition reflects an altered response to LF rTMS in patients with PI. These rTMS findings are indicative of an altered cortical plasticity in inhibitory circuits within M1 in PI. Subjects with PI exhibited an impairment of the LTD-like mechanisms induced by inhibitory rTMS, thus providing further support to the involvement of GABA neurotransmission in the pathophysiology of PI.
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http://dx.doi.org/10.1016/j.sleep.2020.03.030DOI Listing
August 2020

Understanding hyper-reflexia in acute motor axonal neuropathy (AMAN).

Neurophysiol Clin 2020 Jul 25;50(3):139-144. Epub 2020 Jun 25.

Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy.

Hyper-reflexia is occasionally seen in acute motor axonal neuropathy (AMAN), but its pathophysiology is unclear. We report a patient with AMAN following Campylobacter jejuni enteritis, who showed generalized hyper-reflexia, bilateral Hoffmann sign and right Babinski sign. MRI and transcranial magnetic stimulation of the motor cortex disclosed no corticospinal tract involvement. An extensive electrophysiological investigation documented α-motoneuron hyperexcitability and dysfunction of the interneuronal inhibitory circuits in the spinal anterior horn. We propose an immune-mediated damage of the spinal inhibitory interneuronal network as possible mechanism inducing hyper-reflexia in AMAN.
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http://dx.doi.org/10.1016/j.neucli.2020.05.004DOI Listing
July 2020

Jean-Martin Charcot´s medical instruments: Electrotherapeutic devices in .

J Hist Neurosci 2021 Jan-Mar;30(1):94-101. Epub 2020 Jun 18.

Independent Researcher , Brou, France.

In the famous painting (A Clinical Lesson at the Salpêtrière) by André Brouillet (1857-1914), the neurologist Jean-Martin Charcot (1825-1893) is shown delivering a clinical lecture in front of a large audience. A hysterical patient, Marie Wittman (known as "Blanche"; 1859-1912) is leaning against Charcot's pupil, Joseph Babinski (1857-1932). Lying on the table close to Charcot are some medical instruments, traditionally identified as a Duchenne electrotherapy apparatus and a reflex hammer. A closer look at these objects reveals that they should be identified instead as a Du Bois-Reymond apparatus with a Grenet cell (bichromate cell) battery and its electrodes. These objects reflect the widespread practice of electrotherapeutic faradization at the Salpêtrière. Furthermore, they allow us to understand the moment depicted in the painting: contrary to what is sometimes claimed, Blanche has not been represented during a hysterical attack, but during a moment of hypnotically induced lethargy.
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http://dx.doi.org/10.1080/0964704X.2020.1775391DOI Listing
June 2020

Prediction of Cognitive Decline in Temporal Lobe Epilepsy and Mild Cognitive Impairment by EEG, MRI, and Neuropsychology.

Comput Intell Neurosci 2020 20;2020:8915961. Epub 2020 May 20.

Department of Neurology, Centre for Cognitive Neuroscience, Paracelsus Medical University, Salzburg, Austria.

Cognitive decline is a severe concern of patients with mild cognitive impairment. Also, in patients with temporal lobe epilepsy, memory problems are a frequently encountered problem with potential progression. On the background of a unifying hypothesis for cognitive decline, we merged knowledge from dementia and epilepsy research in order to identify biomarkers with a high predictive value for cognitive decline across and beyond these groups that can be fed into intelligent systems. We prospectively assessed patients with temporal lobe epilepsy ( = 9), mild cognitive impairment ( = 19), and subjective cognitive complaints ( = 4) and healthy controls ( = 18). All had structural cerebral MRI, EEG at rest and during declarative verbal memory performance, and a neuropsychological assessment which was repeated after 18 months. Cognitive decline was defined as significant change on neuropsychological subscales. We extracted volumetric and shape features from MRI and brain network measures from EEG and fed these features alongside a baseline testing in neuropsychology into a machine learning framework with feature subset selection and 5-fold cross validation. Out of 50 patients, 27 had a decline over time in executive functions, 23 in visual-verbal memory, 23 in divided attention, and 7 patients had an increase in depression scores. The best sensitivity/specificity for decline was 72%/82% for executive functions based on a feature combination from MRI volumetry and EEG partial coherence during recall of memories; 95%/74% for visual-verbal memory by combination of MRI-wavelet features and neuropsychology; 84%/76% for divided attention by combination of MRI-wavelet features and neuropsychology; and 81%/90% for increase of depression by combination of EEG partial directed coherence factor at rest and neuropsychology. Combining information from EEG, MRI, and neuropsychology in order to predict neuropsychological changes in a heterogeneous population could create a more general model of cognitive performance decline.
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http://dx.doi.org/10.1155/2020/8915961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256687PMC
April 2021

Functional connectivity after hemispherectomy.

Quant Imaging Med Surg 2020 May;10(5):1174-1178

Franz Tappeiner Hospital, Merano, Italy.

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http://dx.doi.org/10.21037/qims.2020.03.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242305PMC
May 2020

Cannabidiol efficacy and clobazam status: A systematic review and meta-analysis.

Epilepsia 2020 06 26;61(6):1090-1098. Epub 2020 May 26.

Department of Neuroscience, Biomedicine, and Movement Science, University of Verona, Verona, Italy.

Objective: To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut syndrome using meta-analytical techniques.

Methods: We searched for randomized, placebo-controlled, single- or double-blinded trials. The proportion of patients who achieved ≥50% reduction from baseline in seizure frequency during the treatment period was assessed according to CLB status. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated.

Results: Four trials were included and enrolled 714 participants, 429 for the add-on CBD group and 285 for the add-on placebo group. Among CBD-treated patients, 240 (55.9%) were taking concomitant CLB (CLB-On) and 189 (44.1%) were not taking concomitant CLB (CLB-Off); in placebo-treated patients, 158 (55.4%) were CLB-On and 127 (44.6%) CLB-Off. The percentages of patients who had at least 50% reduction in seizure frequency during the treatment period were 29.1% in the CBD arm and 15.7% in the placebo group among CLB-Off patients (RR = 1.80, 95% CI = 1.12-2.90, P = .015). Among CBL-On patients, the ≥50% reduction in seizure frequency was found in 52.9% and 27.8% in the CBD and placebo groups, respectively (RR = 1.85, 95% CI = 1.40-2.44, P < .001).

Significance: CBD was associated with a higher rate of seizure response in comparison to placebo when added to the existing antiepileptic regimen both in patients taking and in those not taking concomitant CLB. The lack of randomization for CLB status and the limited sample size need to be considered in the interpretation of the findings.
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http://dx.doi.org/10.1111/epi.16546DOI Listing
June 2020

Functional Magnetic Resonance Imaging in the Final Stage of Creutzfeldt-Jakob Disease.

Diagnostics (Basel) 2020 May 15;10(5). Epub 2020 May 15.

Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, 5020 Salzburg, Austria.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare fatal degenerative disease of the central nervous system. The clinical course is characterized by rapid progression of neurological and neuromuscular symptoms. The late stage with loss of consciousness is not well characterized. We report a 62-year-old male patient with sCJD with the clinical picture of a vegetative state/apallic syndrome, in whom we studied cortical responses using a vibration paradigm. The functional magnetic resonance imaging (fMRI) investigation demonstrated a clear response within the sensorimotor cortex, the cerebellum, the parietal cortex, the insular, and frontal inferior region. The finding of persistent cortical activity on fMRI in a patient with CJD in a state of unconsciousness has implications for the clinical management and for ethical considerations.
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http://dx.doi.org/10.3390/diagnostics10050309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277986PMC
May 2020

Effects of Rubber Hand Illusion and Excitatory Theta Burst Stimulation on Tactile Sensation: A Pilot Study.

Neural Plast 2020 1;2020:3069639. Epub 2020 Apr 1.

Department of Neurology and Neuroscience Institute, Christian Doppler University Hospital, Spinal Cord Injury and Tissue Regeneration Center, PMU, Salzburg, Austria.

Synchronous visuotactile stimulation on the own hidden hand and a visible fake limb can alter bodily self-perception and influence spontaneous neuroplasticity. The rubber hand illusion (RHI) paradigm experimentally produces an illusion of rubber hand ownership and arm shift by simultaneously stroking a rubber hand in view and a participant's visually occluded hand. The aim of this cross-over, placebo-controlled, single-blind study was to assess whether RHI, in combination with high-frequency repetitive transcranial magnetic stimulation (rTMS) given as intermittent (excitatory) theta burst stimulation (iTBS) applied over the hand area of the primary sensory region (S1) can enhance tactile sensation in a group of 21 healthy subjects and one patient with cervical spinal cord injury. Four sessions covered all combinations of real and sham stimulations of the RHI and the TBS: real TBS and real RHI, real TBS and sham RHI, sham TBS and real RHI, and both conditions sham. The condition sham TBS and real RHI shows the greatest effect on the proprioceptive drift (median 2.3 cm, IQR 2) and on the score of RHI questionnaires (median 3, IQR 2) in the control group as well as in the real-real condition (median 2, IQR 2). The sham TBS and real RHI condition also shows the best results in the electrical perception test of the patient (median 1.9 mA). Conversely, the upregulation of the cortical excitability of S1 via TBS seems to impair the effect of the RHI. This might be due to a strengthening of the top-down connection between the central nervous system and the periphery, diminishing the RHI. This finding helps in understanding the mechanisms of top-down and bottom-up mechanisms in healthy subjects and patients with spinal cord injury. The RHI paradigm could represent an interesting therapeutic approach in improving tactile sensation and rTMS techniques could modulate these effects. Yet, further studies are needed, to examine the direction of the interaction effect of TMS and RH.
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http://dx.doi.org/10.1155/2020/3069639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152971PMC
April 2021

Repetitive transcranial magnetic stimulation in traumatic brain injury: Evidence from animal and human studies.

Brain Res Bull 2020 06 3;159:44-52. Epub 2020 Apr 3.

Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria; Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria; University for Medical Informatics and Health Technology, UMIT, Hall in Tirol, Austria.

We provide here the first systematic review on the studies dealing with repetitive transcranial magnetic stimulation (rTMS) for traumatic brain injury (TBI) in animals and humans. Several experimental studies in animal models have explored with promising results the use of rTMS to enhance neuroprotection and recovery after TBI. However, there are surprisingly few studies that have obtained substantial evidence regarding effects of rTMS in humans with TBI, many of them are case reports investigating the heterogeneous conditions linked to TBI. The most studies have investigated the effects of rTMS in subjects with post-traumatic depression and variable effects have been observed. rTMS has been proposed as an experimental approach for the treatment of disorders of consciousness (DOC), but in subjects with TBI therapeutic effects on DOC have also been variously documented. Beneficial effects have been reported in subjects with cognitive/emotional disturbances and auditory dysfunction (tinnitus and hallucinations), although the results are somewhat conflicting. rTMS applied over the left prefrontal cortex may relieve, at least transiently, post-traumatic headache. Isolated rTMS studies have been performed in TBI patients with motor impairment, chronic dizziness or pain. Especially whether provided in combination, rTMS and neurorehabilitation may be synergistic in the potential to translate experimental findings in the clinical practice. In order to reach definitive conclusions, well-designed randomized controlled studies with larger patient samples, improved design and optimized rTMS setup, are warranted to verify and corroborate the initial promising findings.
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http://dx.doi.org/10.1016/j.brainresbull.2020.03.016DOI Listing
June 2020

Second-line treatments in benzodiazepine-resistant convulsive status epilepticus: An updated network meta-analysis including the ESET Trial - What did change?

Epilepsy Behav 2020 05 23;106:107035. Epub 2020 Mar 23.

Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy.

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http://dx.doi.org/10.1016/j.yebeh.2020.107035DOI Listing
May 2020

Effects of repetitive transcranial magnetic stimulation in subjects with sleep disorders.

Sleep Med 2020 07 19;71:113-121. Epub 2020 Feb 19.

Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria; Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria; University for Medical Informatics and Health Technology, UMIT, Hall in Tirol, Austria.

In this review, we aimed at identifying the studies that have employed repetitive transcranial magnetic stimulation (rTMS) in patients with sleep disorders. Low-frequency (LF) rTMS stimulating the right dorsolateral prefrontal cortex (DLPFC) or the posterior parietal cortex (PPC) was found to be effective to reduce cortical hyperexcitability and improve the sleep quality in subjects with chronic primary insomnia (PI). Both high-frequency (HF) and LF rTMS applied over the primary motor cortex or the supplementary motor cortex seem to have transient beneficial effects in patients with restless legs syndrome (RLS). Stimulation of upper airway muscles during sleep by isolated TMS and by rTMS twitch can improve airflow dynamics in obstructive sleep apnea syndrome (OSAS) patients without arousal. A single case report study indicates that HF rTMS over the left DLPFC might represent an alternative choice for symptom control in narcoleptic patients with cataplexy, and a pilot study also raises the possibility of therapeutic benefits from rTMS in patients with sleep bruxism. rTMS may also exert intrinsic effects on hypersomnia in depressed adolescents. In conclusion, rTMS may contribute to the development of new non-pharmacological therapeutic options for several sleep disorders. rTMS might be useful as therapeutical tool in particular in patients with PI, RLS, OSAS and narcolepsy, while its effect in other sleep disorders (ie, parasomnias) has not yet been explored. rTMS integrated with clinical, sleep-related, and neuroimaging data may represent an effective tool in modulating cortical excitability and inducing short-term synaptic plasticity. Further studies with larger patient samples, repeated sessions, an optimized rTMS setup, and clinical follow-up warranted to verify the initial findings, and to expand clinical and research interest towards neuromodulation in the different sleep disorders.
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http://dx.doi.org/10.1016/j.sleep.2020.01.028DOI Listing
July 2020

Cerebral HSV-1 Vasculitis as a Fatal Complication of Immunosuppression in Non-Hodgkin´s Lymphoma: A Case Report and Review of the Literature.

Pathogens 2020 Mar 5;9(3). Epub 2020 Mar 5.

Department of Neurology, Christian Doppler Medical Center, Paracelsus University Salzburg, 5020 Salzburg, Austria.

Patients with lymphoma are predisposed to infection because of the immunocompromised state related to the disease itself and as a consequence of chemo-/radiotherapy. Here, we report a case of Herpes-simplex virus encephalitis (HSE) in an immunosuppressed patient with splenic marginal zone lymphoma (SMZL), a rare indolent variant of non-Hodgkin´s lymphoma (NHL). The course was complicated febrile neutropenia and HSV-1-related cerebral vasculitis causing progressive ischemic stroke. This case illustrates the expanding spectrum of atypical clinical and radiological manifestations of HSE in patients treated with myelotoxic drugs. Moreover, we summarize the few central nervous system manifestations of SMZL reported in the literature and discuss distinct causes of neurological deterioration in patients with NHL.
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http://dx.doi.org/10.3390/pathogens9030193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157652PMC
March 2020

Disinhibition of sensory cortex in patients with amyotrophic lateral sclerosis.

Neurosci Lett 2020 03 22;722:134860. Epub 2020 Feb 22.

Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria; Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria; University for Medical Informatics and Health Technology, UMIT, Hall in Tirol, Austria.

In patients with amyotrophic lateral sclerosis (ALS) a motor cortical hyperexcitability has been reported in transcranial magnetic stimulation studies, but little is known about the neuronal excitability in other cortical areas. The aim of the present study was the functional evaluation of the sensory cortex in subjects with ALS by assessing the high-frequency somatosensory evoked potentials (HF-SEP). No significant HF-SEP abnormalities were observed in ALS patients with disease duration of <2 years, while the patients with a disease duration of>2 years we found a large amplitude reduction of post-synaptic HF-SEP burst. Since post-synaptic burst of HF-SEP is thought to reflect the activity of cortical inhibitory interneurons, our findings provide further evidence that disinhibition is a primary characteristic of ALS that also involves the somatosensory cortex.
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http://dx.doi.org/10.1016/j.neulet.2020.134860DOI Listing
March 2020

Contribution of transcranial magnetic stimulation in restless legs syndrome: pathophysiological insights and therapeutical approaches.

Sleep Med 2020 07 24;71:124-134. Epub 2019 Dec 24.

Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria; Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria; University for Medical Informatics and Health Technology, UMIT, Hall in Tirol, Austria.

Transcranial magnetic stimulation (TMS) may offer a reliable means to characterize significant pathophysiologic and neurochemical aspects of restless legs syndrome (RLS). Namely, TMS has revealed specific patterns of changes in cortical excitability and plasticity, in particular dysfunctional inhibitory mechanisms and sensorimotor integration, which are thought to be part of the pathophysiological mechanisms of RLS rather than reflect a non-specific consequence of sleep architecture alteration. If delivered repetitively, TMS is able to transiently modulate the neural activity of the stimulated and connected areas. Some studies have begun to therapeutically use repetitive TMS (rTMS) to improve sensory and motor disturbances in RLS. High-frequency rTMS applied over the primary motor cortex or the supplementary motor cortex, as well as low-frequency rTMS over the primary somatosensory cortex, seem to have transient beneficial effects. However, further studies with larger patient samples, repeated sessions, an optimized rTMS setup, and clinical follow-up are needed in order to corroborate preliminary results. Thus, we performed a systematic search of all the studies that have used TMS and rTMS techniques in patients with RLS.
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http://dx.doi.org/10.1016/j.sleep.2019.12.009DOI Listing
July 2020

Facilitation of Auditory Comprehension After Theta Burst Stimulation of Wernicke's Area in Stroke Patients: A Pilot Study.

Front Neurol 2019 8;10:1319. Epub 2020 Jan 8.

Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria.

Single-pulse transcranial magnetic stimulation (TMS) and high-frequency repetitive TMS (rTMS) over Wernicke's area were found to facilitate language functions in right-handed healthy subjects. We aimed at investigating the effects of excitatory rTMS, given as intermittent theta burst stimulation (iTBS) over left Wernicke's area, on auditory comprehension in patients suffering from fluent aphasia after stroke of the left temporal lobe. We studied 13 patients with chronic fluent aphasia after an ischemic stroke involving Wernicke's area. iTBS was applied in random order to Wernicke's area, the right-hemisphere homologous of Wernicke's area, and the primary visual cortex. Auditory comprehension was blind assessed using the Token test before (T0), 5 (T1), and 40 min (T2) after a single session of iTBS. At the first evaluation (T1) after iTBS on left Wernike's area, but not on the contralateral homologous area nor on the primary visual cortex, the scores on the Token test were significantly increased. No significant effects were observed at T2. We demonstrated that a single session of excitatory iTBS over Wernicke's area was safe and led to a transient facilitation of auditory comprehension in chronic stroke patients with lesions in the same area. Further studies are needed to establish whether TBS-induced modulation can be enhanced and transformed into longer-lasting effects by means of repeated TBS sessions and by combining TBS with speech and language therapy.
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http://dx.doi.org/10.3389/fneur.2019.01319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960103PMC
January 2020