Reply to: "Reflecting the causes of variability of EEG responses elicited by cerebellar TMS".

In their commentary on our recently published paper about electroencephalographic responses induced by cerebellar transcranial magnetic stimulation (Fong et al., 2023), Gassmann and colleagues (Gassmann et al., 2023b) try to explain the differences between our results and their own previous work on the same topic. We agree with them that many of the differences arise from our use of a different magnetic stimulation coil. However, two unresolved questions remain. (1) Which method is most likely to achieve optimal activation of cerebellar output? (2) To what extent are the evoked cerebellar responses contaminated by concomitant sensory input? We highlight the role of careful experimental design and of combining electrophysiological and behavioural data to obtain reliable TMS-EEG data.

Pain-motor integration in chronic pain: A neurophysiological study.

OBJECTIVE: Chronic pain may lead to functional changes in several brain regions, including the primary motor cortex (M1). Our neurophysiological study aimed to probe M1 plasticity, through a non-invasive transcranial magnetic stimulation protocol, in a cohort of patients with chronic pain. METHODS: Twenty patients with chronic pain (age ± SD: 62.9 ± 9.9) and 20 age- and sex-matched healthy controls (age ± SD: 59.6 ± 15.8) were recruited. Standardized scales were used for the evaluation of pain severity. Neurophysiological measures included laser-evoked potentials (LEPs) and motor-evoked potentials (MEPs) collected at baseline and over 60 minutes following a standardized Laser-paired associative stimulation (Laser-PAS) protocol. RESULTS: LEPs and MEPs were comparable in patients with chronic pain and controls. The pain threshold was lower in patients than in controls. Laser-PAS elicited decreased responses in patients with chronic pain. The response to Laser-PAS was similar in subgroups of patients with different chronic pain phenotypes. CONCLUSIONS: M1 plasticity, as tested by Laser-PAS, is altered in patients with chronic pain, possibly reflecting abnormal pain-motor integration processes. SIGNIFICANCE: Chronic pain is associated with a disorder of M1 plasticity raising from abnormal pain-motor integration.

Pathophysiology, Functional Assessment and Prognostic Implications of Nutritional Disorders in Systemic Amyloidosis.

Gastrointestinal involvement is a common clinical feature of patients with systemic amyloidosis. This condition is responsible for invalidating gastrointestinal symptoms, a significant macro and micronutrient deficit, and is a marker of disease severity. Gastrointestinal involvement should be actively sought in patients with systemic amyloidosis, while its diagnosis is challenging in patients with isolated gastrointestinal symptoms. The nutritional status in systemic amyloidosis plays an essential role in the clinical course and is considered a significant prognostic factor. However, the definition of nutritional status is still challenging due to the lack of internationally accepted thresholds for anthropometric and biochemical variables, especially in specific populations such as those with systemic amyloidosis. This review aims to elucidate the fundamental steps for nutritional assessment by using clinical and instrumental tools for better prognostic stratification and patient management regarding quality of life and outcomes.

Dystonia Diagnosis: Clinical Neurophysiology and Genetics.

Dystonia diagnosis is based on clinical examination performed by a neurologist with expertise in movement disorders. Clues that indicate the diagnosis of a movement disorder such as dystonia are dystonic movements, dystonic postures, and three additional physical signs (mirror dystonia, overflow dystonia, and geste antagonists/sensory tricks). Despite advances in research, there is no diagnostic test with a high level of accuracy for the dystonia diagnosis. Clinical neurophysiology and genetics might support the clinician in the diagnostic process. Neurophysiology played a role in untangling dystonia pathophysiology, demonstrating characteristic reduction in inhibition of central motor circuits and alterations in the somatosensory system. The neurophysiologic measure with the greatest evidence in identifying patients affected by dystonia is the somatosensory temporal discrimination threshold (STDT). Other parameters need further confirmations and more solid evidence to be considered as support for the dystonia diagnosis. Genetic testing should be guided by characteristics such as age at onset, body distribution, associated features, and coexistence of other movement disorders (parkinsonism, myoclonus, and other hyperkinesia). The aim of the present review is to summarize the state of the art regarding dystonia diagnosis focusing on the role of neurophysiology and genetic testing.

Classification of Dystonia.

Dystonia is a hyperkinetic movement disorder characterized by abnormal movement or posture caused by excessive muscle contraction. Because of its wide clinical spectrum, dystonia is often underdiagnosed or misdiagnosed. In clinical practice, dystonia could often present in association with other movement disorders. An accurate physical examination is essential to describe the correct phenomenology. To help clinicians reaching the proper diagnosis, several classifications of dystonia have been proposed. The current classification consists of axis I, clinical characteristics, and axis II, etiology. Through the application of this classification system, movement disorder specialists could attempt to correctly characterize dystonia and guide patients to the most effective treatment. The aim of this article is to describe the phenomenological spectrum of dystonia, the last approved dystonia classification, and new emerging knowledge.

Two forms of short-interval intracortical inhibition in human motor cortex.

BACKGROUND: Pulses of transcranial magnetic stimulation (TMS) with a predominantly anterior-posterior (AP) or posterior-anterior (PA) current direction over the primary motor cortex appear to activate distinct excitatory inputs to corticospinal neurons. In contrast, very few reports have examined whether the inhibitory neurons responsible for short-interval intracortical inhibition (SICI) are sensitive to TMS current direction. OBJECTIVES: To investigate whether SICI evaluated with AP and PA conditioning stimuli (CSPA and CSAP) activate different inhibitory pathways. SICI was always assessed using a PA-oriented test stimulus (TSPA). METHODS: Using two superimposed TMS coils, CSPA and CSAP were applied at interstimulus intervals (ISI) of 1-5 ms before a TSPA, and at a range of different intensities. Using a triple stimulation design, we then tested whether SICI at ISI of 3 ms using opposite directions of CS (SICICSPA3 and SICICSAP3) interacted differently with three other forms of inhibition, including SICI at ISI of 2 ms (SICICSPA2), cerebellum-motor cortex inhibition (CBI 5 ms) and short-latency afferent inhibition (SAI 22 ms). Finally, we compared the effect of tonic and phasic voluntary contraction on SICICSPA3 and SICICSAP3. RESULTS: CSAP produced little SICI at ISIs = 1 and 2 ms. However, at ISI = 3 ms, both CSAP and CSPA were equally effective at the same percent of maximum stimulator output. Despite this apparent similarity, combining SICICSPA3 or SICICSAP3 with other forms of inhibition led to quite different results: SICICSPA3 interacted in complex ways with CBI, SAI and SICICSPA2, whereas the effect of SICICSAP3 appeared to be quite independent of them. Although SICICSPA and SICICSAP were both reduced by the same amount during voluntary tonic contraction compared with rest, in a simple reaction time task SICICSAP was disinhibited much earlier following the imperative signal than SICICSPA. CONCLUSIONS: SICICSPA appears to activate a different inhibitory pathway to that activated by SICICSAP. The difference is behaviourally relevant since the pathways are controlled differently during volitional contraction. The results may explain some previous pathological data and open the possibility of testing whether these pathways are differentially recruited in a range of tasks.

Disentangling EEG responses to TMS due to cortical and peripheral activations.

BACKGROUND: the use of combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) for the functional evaluation of the cerebral cortex in health and disease is becoming increasingly common. However, there is still some ambiguity regarding the extent to which brain responses to auditory and somatosensory stimulation contribute to the TMS-evoked potential (TEP). OBJECTIVE/HYPOTHESIS: to measure separately the contribution of auditory and somatosensory stimulation caused by TMS, and to assess their contribution to the TEP waveform, when stimulating the motor cortex (M1). METHODS: 19 healthy volunteers underwent 7 blocks of EEG recording. To assess the impact of auditory stimulation on the TEP waveform, we used a standard figure of eight coil, with or without masking with a continuous noise reproducing the specific time-varying frequencies of the TMS click, stimulating at 90% of resting motor threshold. To further characterise auditory responses due to the TMS click, we used either a standard or a sham figure of eight coil placed on a pasteboard cylinder that rested on the scalp, with or without masking. Lastly, we used electrical stimulation of the scalp to investigate the possible contribution of somatosensory activation. RESULTS: auditory stimulation induced a known pattern of responses in electrodes located around the vertex, which could be suppressed by appropriate noise masking. Electrical stimulation of the scalp alone only induced similar, non-specific scalp responses in the in the central electrodes. TMS, coupled with appropriate masking of sensory input, resulted in specific, lateralized responses at the stimulation site, lasting around 300 ms. CONCLUSIONS: if careful control of confounding sources is applied, TMS over M1 can generate genuine, lateralized EEG activity. By contrast, sensory evoked responses, if present, are represented by non-specific, late (100-200 ms) components, located at the vertex, possibly due to saliency of the stimuli. Notably, the latter can confound the TEP if masking procedures are not properly used.

Gait Analysis in Parkinson's Disease: An Overview of the Most Accurate Markers for Diagnosis and Symptoms Monitoring.

The aim of this review is to summarize that most relevant technologies used to evaluate gait features and the associated algorithms that have shown promise to aid diagnosis and symptom monitoring in Parkinson's disease (PD) patients. We searched PubMed for studies published between 1 January 2005, and 30 August 2019 on gait analysis in PD. We selected studies that have either used technologies to distinguish PD patients from healthy subjects or stratified PD patients according to motor status or disease stages. Only those studies that reported at least 80% sensitivity and specificity were included. Gait analysis algorithms used for diagnosis showed a balanced accuracy range of 83.5-100%, sensitivity of 83.3-100% and specificity of 82-100%. For motor status discrimination the gait analysis algorithms showed a balanced accuracy range of 90.8-100%, sensitivity of 92.5-100% and specificity of 88-100%. Despite a large number of studies on the topic of objective gait analysis in PD, only a limited number of studies reported algorithms that were accurate enough deemed to be useful for diagnosis and symptoms monitoring. In addition, none of the reported algorithms and technologies has been validated in large scale, independent studies.

Detecting cortical circuits resonant to high-frequency oscillations in the human primary motor cortex: a TMS-tACS study.

Corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) consist of high-frequency bursts (≈667 and ≈333 Hz). However, intracortical circuits producing such corticospinal high-frequency bursts are unknown. We here investigated whether neurons activated by single TMS pulses over M1 are resonant to high-frequency oscillations, using a combined transcranial alternating current stimulation (tACS)-TMS approach. We applied 667, 333 Hz or sham-tACS and, concurrently, we delivered six single-pulse TMS protocols using monophasic or biphasic pulses, different stimulation intensities, muscular states, types and orientations of coils. We recorded motor evoked potentials (MEPs) before, during and after tACS. 333 Hz tACS facilitated MEPs evoked by biphasic TMS through a figure-of-eight coil at active motor threshold (AMT), and by monophasic TMS with anterior-to-posterior-induced current in the brain. 333 Hz tACS also facilitated MEPs evoked by monophasic TMS through a circular coil at AMT, an effect that weakly persisted after the stimulation. 667 Hz tACS had no effects. 333 Hz, but not 667 Hz, tACS may have reinforced the synchronization of specific neurons to high-frequency oscillations enhancing this activity, and facilitating MEPs. Our findings suggest that different bursting modes of corticospinal neurons are produced by separate circuits with different oscillatory properties.

Pseudoagoraphobia, a Diagnostic Clue in Stiff-Limb Syndrome.

BACKGROUND: Stiff-limb syndrome is part of stiff person spectrum, presenting with fluctuating gait disorders attributed to leg stiffness, spasms, and posturing. It could also manifest with anxiety and specific phobias such as pseudoagoraphobia. We aimed to describe the importance of specific gait phobia as a diagnostic clue to anti-glutamic acid decarboxylase stiff-limb syndrome. CASES: We reported on 2 cases of stiff-limb syndrome sharing a similar diagnostic path and phenomenology. Both were featured by pseudoagoraphobia, which has documented to typically cover organic conditions, and a remarkable diagnostic delay attributed to misdiagnoses. Presence of pseudoagoraphobia should not point to the diagnosis of a functional disorder-although a negative instrumental workup is documented. CONCLUSIONS: Both cases are emblematic of the high misdiagnosis rate affecting stiff person syndrome patients. A proper diagnostic process, including the identification of a pseudoagoraphobia, should help in reaching a diagnosis and providing an early and effective treatment.

Complex dyskinesias in Parkinson patients on levodopa/carbidopa intestinal gel.

BACKGROUND: Levodopa-carbidopa intestinal infusion is an effective treatment for motor fluctuations in Parkinson's disease. However, it has been recently associated with emergent complex/atypical dyskinesias. We sought to characterize patients who developed these dyskinesias after levodopa infusion initiation, and to compare these patients to a control population with conventional motor fluctuations. METHODS: 208 Parkinson's disease patients, treated with levodopa intestinal infusion due to motor fluctuations, were screened for onset and/or worsening of dyskinesias after initiation of levodopa infusion, resistant to the routine titration, and presenting with atypical or unexpected patterns. Patients with extensive follow-up data were enrolled for a longitudinal analysis. Cases were compared to a control sample with conventional motor fluctuations in order to investigate predisposing factors, difference in dyskinesia phenotype, management strategies and dropouts. RESULTS: Thirty patients out of 208 (14.4%) reported atypical (i.e. long-lasting) biphasic, biphasic-like (i.e. continuous) or mixed (peak-dose and continuous biphasic) dyskinesias after levodopa infusion. They were compared at baseline and follow-up to a sample of 49 patients with conventional motor fluctuations on levodopa infusion. Both groups had similar demographic and clinical features, except the former having higher prevalence of biphasic dyskinesias while on oral therapy. Biphasic-like dyskinesias in nearly half the number of cases improved with increasing the dopaminergic load, while mixed dyskinesias had the worst outcome and highest dropout rate (58%). CONCLUSIONS: Atypical biphasic, biphasic-like and complex dyskinesias could hinder the course of patients treated with levodopa infusion. This study further informs the selection process of advanced therapies, particularly in dyskinetic patients.

Transcutaneous Vagus Nerve Stimulation Combined with Robotic Rehabilitation Improves Upper Limb Function after Stroke.

The efficacy of standard rehabilitative therapy for improving upper limb functions after stroke is limited; thus, alternative strategies are needed. Vagus nerve stimulation (VNS) paired with rehabilitation is a promising approach, but the invasiveness of this technique limits its clinical application. Recently, a noninvasive method to stimulate vagus nerve has been developed. The aim of the present study was to explore whether noninvasive VNS combined with robotic rehabilitation can enhance upper limb functionality in chronic stroke. Safety and efficacy of this combination have been assessed within a proof-of-principle, double-blind, semirandomized, sham-controlled trial. Fourteen patients with either ischemic or haemorrhagic chronic stroke were randomized to robot-assisted therapy associated with real or sham VNS, delivered for 10 working days. Efficacy was evaluated by change in upper extremity Fugl-Meyer score. After intervention, there were no adverse events and Fugl-Meyer scores were significantly better in the real group compared to the sham group. Our pilot study confirms that VNS is feasible in stroke patients and can produce a slight clinical improvement in association to robotic rehabilitation. Compared to traditional stimulation, noninvasive VNS seems to be safer and more tolerable. Further studies are needed to confirm the efficacy of this innovative approach.

The Clinical Course of a Drug-induced Acute Dystonic Reaction in the Emergency Room.

BACKGROUND: Acute dystonic reactions following the administration of safe, reliable drugs can occur and must be promptly recognized and treated in the emergency room. PHENOMENOLOGY SHOWN: The entire clinical course of an acute dystonic reaction due to metoclopramide, from early motor signs to full-blown clinical symptoms and resolution. EDUCATIONAL VALUE: Providing elements for early recognition of a drug-induced movement disorder phenomenology.