Cerebellar ataxias are a heterogenous group of degenerative disorders for which we currently lack effective and disease-modifying interventions. The field of non-invasive brain stimulation has made ...much progress in the development of specific stimulation protocols to modulate cerebellar excitability and try to restore the physiological activity of the cerebellum in patients with ataxia. In light of limited evidence-based pharmacologic and non-pharmacologic treatment options for patients with ataxia, several different non-invasive brain stimulation protocols have emerged, particularly employing repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) techniques. In this review, we summarize the most relevant rTMS and tDCS therapeutic trials and discuss their implications in the care of patients with degenerative ataxias.
Abstract
Background
Several preclinical and clinical investigations have argued for nervous system involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some sparse ...case reports have described various forms of encephalitis in coronavirus disease 2019 (COVID-19) disease, but very few data have focused on clinical presentations, clinical course, response to treatment, and outcomes.
Methods
The SARS-CoV-2 related encephalopaties (ENCOVID) multicenter study included patients with encephalitis with full infectious screening, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) data and confirmed SARS-CoV-2 infection recruited from 13 centers in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment, and outcomes were recorded.
Results
Twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction resulted negative. Based on MRI, cases were classified as acute demyelinating encephalomyelitis (ADEM; n = 3), limbic encephalitis (LE; n = 2), encephalitis with normal imaging (n = 13), and encephalitis with MRI alterations (n = 7). ADEM and LE cases showed a delayed onset compared to the other encephalitis cases (P = .001) and were associated with previous, more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to those with other encephalitis.
Conclusions
SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment, and outcomes.
In this prospective multicenter study including 25 cases of encephalitis in severe acute respiratory syndrome coronavirus 2 infection, the majority of patients presented clinical, imaging, and cerebrospinal fluid findings, arguing for a cytokine-mediated mechanism.
Presymptomatic carriers of GRN and C9orf72 mutations, the most frequent genetic causes of frontotemporal lobar degeneration, represent the optimal target population for the development of ...disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. We assessed clinical, functional, and neurophysiological measures in 113 GRN or C9orf72 carriers and in 73 noncarrier first-degree relatives. For 73 patients, follow-up longitudinal data were available. Differences between carriers and noncarriers were assessed using linear mixed-effects models. We observed that biological changes and intracortical facilitation transmission abnormalities significantly antecede the emergence of clinical symptoms of at least 3 decades. These are followed by intracortical inhibition transmission deficits, detected approximately 2 decades before expected symptom onset and then followed by an increase of white matter lesions, structural brain atrophy, and cognitive impairment. These results highlight how several biomarkers can show different aspects and rates of decline, possibly correlated with the underlying physiopathological process, that arise decades before the onset of clinical symptoms.
•FTD mutation carriers provide a window of opportunity into the earliest stages of disease.•TMS allows the evaluation of intracortical circuits which have been shown to be altered in FTD.•Intracortical connectivity changes were detected at more than 30 years before symptom onset.•Subsequently, white matter lesions, brain atrophy and cognitive impairment becomes manifest.
To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex ...and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer’s disease (MCI-AD).
In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated.
Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 95% CI, 4.0 to 7.4, p < 0.001) and long delayed recall scores (1.3 95% CI, 0.4 to 2.1, p = 0.007) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ−tACS (4.3 95% CI, 2.8 to 5.8, p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after γ-tACS (0.31 95% CI, 0.24 to 0.38, p < 0.001) but not after sham tACS.
exposure to γ-tACS over Pz showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS.
•Randomized, double-blind, sham controlled, cross-over study of γ-tACS in MCI-AD.•Improvement at the Rey auditory verbal learning after γ-tACS.•Short latency afferent inhibition increased after γ-tACS.
•This review presents the contribution of TMS to the management of dementia.•TMS can be used as a biomarker of the excitability and function of cerebral cortex in dementia.•Increasing evidence ...supports the beneficial effects of rTMS in Alzheimer’s disease-related dementias at mild/early stage.
Transcranial magnetic stimulation (TMS) is a powerful tool to probe in vivo brain circuits, as it allows to assess several cortical properties such asexcitability, plasticity and connectivity in humans. In the last 20 years, TMS has been applied to patients with dementia, enabling the identification of potential markers of thepathophysiology and predictors of cognitive decline; moreover, applied repetitively, TMS holds promise as a potential therapeutic intervention.
The objective of this paper is to present a comprehensive review of studies that have employed TMS in dementia and to discuss potential clinical applications, from the diagnosis to the treatment.
To provide a technical and theoretical framework, we first present an overview of the basic physiological mechanisms of the application of TMS to assess cortical excitability, excitation and inhibition balance, mechanisms of plasticity and cortico-cortical connectivity in the human brain. We then review the insights gained by TMS techniques into the pathophysiology and predictors of progression and response to treatment in dementias, including Alzheimer’s disease (AD)-related dementias and secondary dementias. We show that while a single TMS measure offers low specificity, the use of a panel of measures and/or neurophysiological index can support the clinical diagnosis and predict progression.
In the last part of the article, we discuss the therapeutic uses of TMS. So far, only repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex and multisite rTMS associated with cognitive training have been shown to be, respectively, possibly (Level C of evidence) and probably (Level B of evidence) effective to improve cognition, apathy, memory, and language in AD patients, especially at a mild/early stage of the disease. The clinical use of this type of treatment warrants the combination of brain imaging techniques and/or electrophysiological tools to elucidate neurobiological effects of neurostimulation and to optimally tailor rTMS treatment protocols in individual patients or specific patient subgroups with dementia or mild cognitive impairment.
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
Cerebellar ataxias represent a heterogeneous group of disabling disorders characterized by motor and cognitive disturbances, for which no effective treatment is currently available. In this ...randomized, double-blind, sham-controlled trial, followed by an open-label phase, we investigated whether treatment with cerebello-spinal transcranial direct current stimulation (tDCS) could improve both motor and cognitive symptoms in patients with neurodegenerative ataxia at short and long-term. Sixty-one patients were randomized in two groups for the first controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS) while Group 2 received anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks (T1), with a 12-week (T2) follow-up (randomized, double-blind, sham controlled phase). At the 12-week follow-up (T2), all patients (Group 1 and Group 2) received a second treatment of anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks, with a 14-week (T3), 24-week (T4), 36-week (T5) and 52-week follow-up (T6) (open-label phase). At each time point, a clinical, neuropsychological and neurophysiological evaluation was performed. Cerebellar-motor cortex connectivity was evaluated using transcranial magnetic stimulation. We observed a significant improvement in all motor scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale), in cognition (evaluated with the cerebellar cognitive affective syndrome scale), in quality-of-life scores, in motor cortex excitability and in cerebellar inhibition after real tDCS compared to sham stimulation and compared to baseline (T0), both at short and long-term. We observed an addon-effect after two repeated treatments with real tDCS compared to a single treatment with real tDCS. The improvement at motor and cognitive scores correlated with the restoration of cerebellar inhibition evaluated with transcranial magnetic stimulation. Cerebello-spinal tDCS represents a promising therapeutic approach for both motor and cognitive symptoms in patients with neurodegenerative ataxia, a still orphan disorder of any pharmacological intervention.
OBJECTIVE:To determine whether a transcranial magnetic stimulation (TMS) multiparadigm approach can be used to distinguish Alzheimer disease (AD) from frontotemporal dementia (FTD).
...METHODS:Paired-pulse TMS was used to investigate short-interval intracortical inhibition (SICI) and facilitation (ICF), long-interval intracortical inhibition, and short-latency afferent inhibition (SAI) to measure the activity of different intracortical circuits in patients with AD, patients with FTD, and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operating curve analysis.
RESULTS:A total of 175 participants met the inclusion criteria. We diagnosed 79 patients with AD, 64 patients with FTD, and 32 HC. We found that while patients with AD are characterized by a specific impairment of SAI, FTD shows a remarkable dysfunction of SICI-ICF intracortical circuits. With the use of the best indexes, TMS differentiated FTD from AD with a sensitivity of 91.8% and specificity of 88.6%, AD from HC with a sensitivity of 84.8% and specificity of 90.6%, and FTD from HC with a sensitivity of 90.2% and specificity of 78.1%. These results were confirmed in patients with mild disease.
CONCLUSIONS:TMS is a noninvasive procedure that reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful additional diagnostic tool for clinical practice.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that TMS measures can distinguish patients with AD from those with FTD.
Frontotemporal dementia (FTD) is a heterogenous neurodegenerative disorder, characterized by diverse clinical presentations, neuropathological characteristics and underlying genetic causes. Emerging ...evidence has shown that FTD is characterized by a series of changes in several neurotransmitter systems, including serotonin, dopamine, GABA and, above all, glutamate. Indeed, several studies have now provided preclinical and clinical evidence that glutamate is key in the pathogenesis of FTD. Animal models of FTD have shown a selective hypofunction in
-methyl
-aspartate (NMDA) and α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, while in patients, glutamatergic pyramidal neurons are depleted in several areas, including the frontal and temporal cortices. Recently, a selective involvement of the AMPA GluA3 subunit has been observed in patients with autoimmune anti-GluA3 antibodies, which accounted for nearly 25% of FTD patients, leading to a decrease of the GluA3 subunit synaptic localization of the AMPA receptor and loss of dendritic spines. Other
evidence of the involvement of the glutamatergic system in FTD derives from non-invasive brain stimulation studies using transcranial magnetic stimulation, in which specific stimulation protocols have indirectly identified a selective and prominent impairment in glutamatergic circuits in patients with both sporadic and genetic FTD. In view of limited disease modifying therapies to slow or revert disease progression in FTD, an important approach could consist in targeting the neurotransmitter deficits, similarly to what has been achieved in Parkinson's disease with dopaminergic therapy or Alzheimer's disease with cholinergic therapy. In this review, we summarize the current evidence concerning the involvement of the glutamatergic system in FTD, suggesting the development of new therapeutic strategies.
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