Changes in cerebellar output abnormally modulate cortical myoclonus sensorimotor hyperexcitability.

Cortical myoclonus is produced by abnormal neuronal discharges within the sensorimotor cortex, as demonstrated by electrophysiology. Our hypothesis is that the loss of cerebellar inhibitory control over the motor cortex, via cerebello-thalamo-cortical connections, could induce the increased sensorimotor cortical excitability that eventually causes cortical myoclonus. To explore this hypothesis, in the present study we applied anodal transcranial direct current stimulation over the cerebellum of patients affected by cortical myoclonus and healthy controls and assessed its effect on sensorimotor cortex excitability. We expected that anodal cerebellar transcranial direct current stimulation would increase the inhibitory cerebellar drive to the motor cortex and therefore reduce the sensorimotor cortex hyperexcitability observed in cortical myoclonus. Ten patients affected by cortical myoclonus of various aetiology and 10 aged-matched healthy control subjects were included in the study. All participants underwent somatosensory evoked potentials, long-latency reflexes and short-interval intracortical inhibition recording at baseline and immediately after 20 min session of cerebellar anodal transcranial direct current stimulation. In patients, myoclonus was recorded by the means of surface EMG before and after the cerebellar stimulation. Anodal cerebellar transcranial direct current stimulation did not change the above variables in healthy controls, while it significantly increased the amplitude of somatosensory evoked potential cortical components, long-latency reflexes and decreased short-interval intracortical inhibition in patients; alongside, a trend towards worsening of the myoclonus after the cerebellar stimulation was observed. Interestingly, when dividing patients in those with and without giant somatosensory evoked potentials, the increment of the somatosensory evoked potential cortical components was observed mainly in those with giant potentials. Our data showed that anodal cerebellar transcranial direct current stimulation facilitates-and does not inhibit-sensorimotor cortex excitability in cortical myoclonus syndromes. This paradoxical response might be due to an abnormal homeostatic plasticity within the sensorimotor cortex, driven by dysfunctional cerebello-thalamo-cortical input to the motor cortex. We suggest that the cerebellum is implicated in the pathophysiology of cortical myoclonus and that these results could open the way to new forms of treatment or treatment targets.

A Combined Panel of Salivary Biomarkers in de novo Parkinson's Disease.

OBJECTIVE: To investigate molecular biomarkers of a-synuclein and tau aggregation, autophagy, and inflammation in the saliva of de novo Parkinson's disease (PD) patients in comparison to healthy subjects (HS), and to correlate molecular data with clinical features of PD patients, in order to establish whether abnormalities of these parameters are associated with specific clusters of de novo PD patients, and their potential diagnostic power in differentiating PD patients from HS. METHODS: We measured total and oligomeric a-synuclein, total-tau and phosphorylated-tau, microtubule-associated protein light chain 3 beta (MAP-LC3beta), and tumor necrosis factor alpha (TNFalpha) in the saliva of 80 de novo PD patients and 62 HS, using quantitative enzyme-linked immunosorbent Assay analysis. RESULTS: Oligomeric a-synuclein, total-tau, MAP-LC3beta, and TNFalpha levels resulted significantly higher in patients with respect to HS, while no significant differences were detected for total a-synuclein or phosphorylated-tau. Phosphorylated-tau directly correlated with MAP-LC3beta, whereas it inversely correlated with TNFalpha in PD patients. An inverse correlation was detected between MAP-LC3beta and non-motor symptoms severity. Principal Component Analysis showed that molecular and clinical parameters were independent of each other in de novo PD patients. Receiver operating characteristic curve analysis reported an accurate diagnostic performance of oligomeric a-synuclein and MAP-LC3beta. The diagnostic accuracy of total a-synuclein increased when it was combined with other salivary biomarkers targeting different molecular pathways. INTERPRETATION: Our study proposes a novel biomarker panel using saliva, a non-invasive biofluid, in de novo PD patients, with implications in understanding the molecular pathways involved in PD pathogenesis and the relevance of different molecular pathways in determining clinical PD subtypes. ANN NEUROL 2023;93:446-459.

Prevalence, treatment, and neural correlates of apathy in different forms of dementia: a narrative review.

OBJECTIVES: The aim of this review is to provide an overview on prevalence and clinical tools for the diagnosis of apathy, as well as on neurophysiological and neuroimaging findings obtained from studies in patients with apathy in different forms of dementia, including Alzheimer's disease (AD), vascular (VaD) and mixed dementia, frontotemporal dementia (FTD), and Parkinson's disease dementia (PDD). METHODS: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series from four databases (WebOfScience, Scopus, Pubmed, and PsycINFO) addressing apathy in adults or older people aged over 65 years of age affected by dementia were included. RESULTS: The prevalence of apathy was 26-82% for AD, 28.6-91.7 for VaD, 29-97.5% in PDD, and 54.8-88.0 in FTD. The assessment of apathy was not consistent in the reviewed studies. Methylphenidate was the most successful pharmacological treatment for apathy. Neurobiological studies highlighted the relationship between both structural and functional brain areas and the presence or severity of apathy. CONCLUSION: Apathy is a very common disorder in all types of dementia, although it is often underdiagnosed and undertreated. Further studies are needed to investigate its diagnosis and management. A consensus on the different evaluation scales should be achieved.

Vibro-tactile stimulation of the neck reduces pain in people with cervical dystonia: a proof-of-concept study.

BACKGROUND: Pain is a common non-motor symptom in patients with cervical dystonia (CD), severely impacting their quality of life. The pathophysiology of CD is incompletely understood but it involves altered processing of proprioceptive and pain signals. OBJECTIVES: The purpose of this proof-of-concept study was to determine if vibro-tactile stimulation (VTS)-a non-invasive form of neuromodulation targeting the somatosensory system-can modulate neck pain in people with CD. METHODS: In a multi-center study, 44 CD patients received VTS to sternocleidomastoid and/or trapezius muscles for up to 45 min under 9 different stimulation conditions that either targeted a single or a pair of muscles. The primary outcome measure was a perceived pain score (PPS) rated by participants on a 100-point analogue scale. RESULTS: During VTS, 29/44 (66%) of participants experienced a reduction in PPS of at least 10% with 17/44 (39%) reporting a reduction in pain of 50% or higher. After VTS cessation, 57% of participants still reported a 10% or higher reduction in PPS. Effects were significant at the group level and persisted for up to 20 min post-treatment. No distinct optimal stimulation profiles were identified for specific CD phenotypes. Clinical markers of disease severity or duration did not predict the degree of VTS-induced pain reduction. CONCLUSION: This proof-of-concept study demonstrates the potential of VTS as a new non-invasive therapeutic option for treating neck pain associated with CD. Further research needs to delineate optimal dosage and long-term effects.

A Novel Paired Somatosensory-Cerebellar Stimulation Induces Plasticity on Cerebellar-Brain Connectivity.

The cerebellum receives and integrates a large amount of sensory information that is important for motor coordination and learning. The aim of the present work was to investigate whether peripheral nerve and cerebellum paired associative stimulation (cPAS) could induce plasticity in both the cerebellum and the cortex. In a cross-over design, we delivered right median nerve electrical stimulation 25 or 10 ms before applying transcranial magnetic stimulation over the cerebellum. We assessed changes in motor evoked potentials (MEP), somatosensory evoked potentials (SEP), short-afferent inhibition (SAI), and cerebellum-brain inhibition (CBI) immediately, and 30 min after cPAS. Our results showed a significant reduction in CBI 30 minutes after cPAS, with no discernible changes in MEP, SEP, and SAI. Notably, cPAS10 did not produce any modulatory effects on these parameters. In summary, cPAS25 demonstrated the capacity to induce plasticity effects in the cerebellar cortex, leading to a reduction in CBI. This novel intervention may be used to modulate plasticity mechanisms and motor learning in healthy individuals and patients with neurological conditions.

Transcranial alternating current stimulation modulates cortical processing of somatosensory information in a frequency- and time-specific manner.

Neural oscillations can be modulated by non-invasive brain stimulation techniques, including transcranial alternating current stimulation (tACS). However, direct evidence of tACS effects at the cortical level in humans is still limited. In a tACS-electroencephalography co-registration setup, we investigated the ability of tACS to modulate cortical somatosensory information processing as assessed by somatosensory-evoked potentials (SEPs). To better elucidate the neural substrates of possible tACS effects we also recorded peripheral and spinal SEPs components, high-frequency oscillations (HFOs), and long-latency reflexes (LLRs). Finally, we studied whether changes were limited to the stimulation period or persisted thereafter. SEPs, HFOs, and LLRs were recorded during tACS applied at individual mu and beta frequencies and at the theta frequency over the primary somatosensory cortex (S1). Sham-tACS was used as a control condition. In a separate experiment, we assessed the time course of mu-tACS effects by recording SEPs before (T0), during (T1), and 1 min (T2) and 10 min (T3) after stimulation. Mu-tACS increased the amplitude of the N20 component of SEPs compared to both sham and theta-tACS. No differences were found between sham, beta-, and theta-tACS conditions. Also, peripheral and spinal SEPs, P25, HFOs, and LLRs did not change during tACS. Finally, mu-tACS-induced modulation of N20 amplitude specifically occurred during stimulation (T1) and vanished afterwards (i.e., at T2 and T3). Our findings suggest that TACS applied at the individual mu frequency is able to modulate early somatosensory information processing at the S1 level and the effect is limited to the stimulation period.

The Pathophysiological Correlates of Parkinson's Disease Clinical Subtypes.

BACKGROUND: Possible pathophysiological mechanisms underlying Parkinson's disease (PD) clinical subtypes are unknown. The objective of this study was to identify pathophysiological substrate of PD subtypes using neurophysiological techniques. METHODS: One hundred de novo PD patients participated. We collected patient demographic and clinical data, which were used to perform a hierarchical cluster analysis. The neurophysiological assessment tested primary motor cortex excitability and plasticity using transcranial magnetic stimulation. To evaluate motor performance, we performed a kinematic analysis of fast index finger abduction. To investigate sensory function and sensorimotor mechanisms, we measured the somatosensory temporal discrimination threshold at rest and during movement, respectively. RESULTS: Hierarchical cluster analysis identified 2 clinical clusters. Cluster I ("mild motor-predominant") included patients who had milder motor and nonmotor symptoms severity than cluster II patients, who had a combination of severe motor and nonmotor manifestations (diffuse malignant). We observed that the diffuse malignant subtype had increased cortical excitability and reduced plasticity compared with the mild motor-predominant subtype. Kinematic analysis of motor performance demonstrated that the diffuse malignant subtype was significantly slower than the mild motor-predominant subtype. Conversely, we did not observe any significant differences in sensory function or sensorimotor integration between the two PD subtypes. CONCLUSIONS: De novo PD subtypes showed different patterns of motor system dysfunction, whereas sensory function and sensorimotor integration mechanisms did not differ between subtypes. Our findings suggest that the subtyping of PD patients is not a mere clinical classification but reflects different pathophysiological mechanisms. Neurophysiological parameters may represent promising biomarkers to evaluate PD subtypes and their progression. © 2020 International Parkinson and Movement Disorder Society.

Happy faces selectively increase the excitability of cortical neurons innervating frowning muscles of the mouth.

Although facial muscles are heavily involved in emotional expressions, there is still a lack of evidence about the role of face primary motor cortex (face M1) in the processing of facial recognition and expression. This work investigated the effects of the passive viewing of different facial expressions on face M1 and compared data with those obtained from the hand M1. Thirty healthy subjects were randomly assigned to two groups undergoing transcranial magnetic stimulation (TMS) of face or hand M1. In both groups, short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF) were probed in the depressor anguli oris (DAO) and first dorsal interosseous (FDI) muscles 300 ms after presentation of a picture of a face that expressed happy, sad or neutral emotions. Statistical analysis of SICI showed a non-significant effect of muscle (F1,28 = 1.903, p = 0.179), but a significant effect of emotion (F2,56 = 6.860, p = 0.004) and a significant interaction between muscle and emotion (F2,56 = 5.072, p = 0.015). Post hoc analysis showed that there was a significant reduction of SICI in the DAO muscle after presentation of a face with a happy expression compared with a neutral face (p < 0.001). In the FDI, a significant difference was observed between neutral and sad expressions (p = 0.010) No clear differences in ICF were detected. The different responses of face and hand muscles to emotional stimuli may be due to their functional roles in emotional expression versus protection of the body.

Abnormal sensory gating in patients with different types of focal dystonias.

BACKGROUND: Movement execution in healthy individuals increases the somatosensory temporal discrimination threshold. These changes are a result of mechanisms of sensory gating at the subcortical level. Although the somatosensory temporal discrimination threshold is abnormally increased in patients with focal dystonias, the effect of movement execution on somatosensory temporal discrimination in dystonic patients is unknown. OBJECTIVES: The objective of this study was to determine whether somatosensory temporal discrimination threshold modulation induced by voluntary movement is normal in different forms of focal dystonia. METHODS: We enrolled 71 dystonic patients (24 with blepharospasm, 31 with cervical dystonia, and 16 with focal hand dystonia) and 39 age-matched healthy participants. Paired stimuli for the somatosensory temporal discrimination threshold were triggered by movement execution at movement onset and at various time intervals thereafter. We analyzed the kinematic features of the motor task to ascertain whether tactile input induces changes in movement parameters. RESULTS: Movement execution led to greater and longer lasting increases in somatosensory temporal discrimination threshold values, both upon movement onset and at various time intervals thereafter, in patients with cervical dystonia and focal hand dystonia than in those with blepharospasm or the healthy participants. Somatosensory temporal discrimination testing did not induce any changes in the mean velocity of index finger movements in either patients or healthy participants. CONCLUSIONS: Somatosensory temporal discrimination threshold changes induced by movement execution are abnormal in focal dystonias. This abnormality is related to the type of dystonia. Abnormal gating of sensory information is likely involved in movement-induced triggering or worsening of different forms focal dystonia. © 2018 International Parkinson and Movement Disorder Society.

Does the Somatosensory Temporal Discrimination Threshold Change over Time in Focal Dystonia?

BACKGROUND: The somatosensory temporal discrimination threshold (STDT) is defined as the shortest interval at which an individual recognizes two stimuli as asynchronous. Some evidence suggests that STDT depends on cortical inhibitory interneurons in the basal ganglia and in primary somatosensory cortex. Several studies have reported that the STDT in patients with dystonia is abnormal. No longitudinal studies have yet investigated whether STDT values in different forms of focal dystonia change during the course of the disease. METHODS: We designed a follow-up study on 25 patients with dystonia (15 with blepharospasm and 10 with cervical dystonia) who were tested twice: upon enrolment and 8 years later. STDT values from dystonic patients at the baseline were also compared with those from a group of 30 age-matched healthy subjects. RESULTS: Our findings show that the abnormally high STDT values observed in patients with focal dystonia remained unchanged at the 8-year follow-up assessment whereas disease severity worsened. CONCLUSIONS: Our observation that STDT abnormalities in dystonia remain unmodified during the course of the disease suggests that the altered activity of inhibitory interneurons-either at cortical or at subcortical level-responsible for the increased STDT does not deteriorate as the disease progresses.

Somatosensory temporal discrimination in essential tremor and isolated head and voice tremors.

The aim of this study was to investigate the somatosensory temporal discrimination threshold in patients with essential tremor (sporadic and familial) and to evaluate whether somatosensory temporal discrimination threshold values differ depending on the body parts involved by tremor. We also investigated the somatosensory temporal discrimination in patients with isolated voice tremor. We enrolled 61 patients with tremor: 48 patients with essential tremor (31 patients with upper limb tremor alone, nine patients with head tremor alone, and eight patients with upper limb plus head tremor; 22 patients with familial vs. 26 sporadic essential tremor), 13 patients with isolated voice tremor, and 45 healthy subjects. Somatosensory temporal discrimination threshold values were normal in patients with familial essential tremor, whereas they were higher in patients with sporadic essential tremor. When we classified patients according to tremor distribution, somatosensory temporal discrimination threshold values were normal in patients with upper limb tremor and abnormal only in patients with isolated head tremor. Temporal discrimination threshold values were also abnormal in patients with isolated voice tremor. Somatosensory temporal discrimination processing is normal in patients with familial as well as in patients with sporadic essential tremor involving the upper limbs. By contrast, somatosensory temporal discrimination is altered in patients with isolated head tremor and voice tremor. This study with somatosensory temporal discrimination suggests that isolated head and voice tremors might possibly be considered as separate clinical entities from essential tremor.

Abnormalities in the face primary motor cortex in oromandibular dystonia.

OBJECTIVE: To comprehensively investigate excitability in face and hand M1 and sensorimotor integration in oromandibular dystonia (OMD) patients. METHODS: Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), short (SAI) and long (LAI) afferent inhibition were investigated in face and hand M1 using transcranial magnetic stimulation protocols in 10 OMD patients. Data were compared with those obtained in 10 patients with focal hand dystonia (FHD), in 10 patients with blepharospasm (BSP), and 10 matched healthy subjects (HS). RESULTS: Results demonstrated that in OMD patients SICI was reduced in face M1 (p < 0.001), but not in hand M1, compared to HS. In FHD, SICI was significantly impaired in hand M1 (p = 0.029), but not in face M1. In BSP, SICI was normal in both face and hand M1 while ICF and LAI were normal in all patient groups and cortical area tested. SAI was significantly reduced (p = 0.003) only in the face M1 of OMD patients. CONCLUSIONS: In OMD, SICI and SAI were significantly reduced. These abnormalities are specific to the motor cortical area innervating the muscular district involved in focal dystonia. SIGNIFICANCE: In OMD, the integration between sensory inflow and motor output seem to be disrupted at cortical level with topographic specificity.

Combining Transcranial Magnetic Stimulation and Deep Brain Stimulation: Current Knowledge, Relevance and Future Perspectives.

Deep brain stimulation (DBS) has emerged as an invasive neuromodulation technique for the treatment of several neurological disorders, but the mechanisms underlying its effects remain partially elusive. In this context, the application of Transcranial Magnetic Stimulation (TMS) in patients treated with DBS represents an intriguing approach to investigate the neurophysiology of cortico-basal networks. Experimental studies combining TMS and DBS that have been performed so far have mainly aimed to evaluate the effects of DBS on the cerebral cortex and thus to provide insights into DBS's mechanisms of action. The modulation of cortical excitability and plasticity by DBS is emerging as a potential contributor to its therapeutic effects. Moreover, pairing DBS and TMS stimuli could represent a method to induce cortical synaptic plasticity, the therapeutic potential of which is still unexplored. Furthermore, the advent of new DBS technologies and novel treatment targets will present new research opportunities and prospects to investigate brain networks. However, the application of the combined TMS-DBS approach is currently limited by safety concerns. In this review, we sought to present an overview of studies performed by combining TMS and DBS in neurological disorders, as well as available evidence and recommendations on the safety of their combination. Additionally, we outline perspectives for future research by highlighting knowledge gaps and possible novel applications of this approach.

Cortical mechanisms of sensory trick in cervical dystonia.

Patients with cervical dystonia (CD) often show an improvement in dystonic posture after sensory trick (ST), though the mechanisms underlying ST remain unclear. In this study, we aimed to investigate the effects of ST on cortical activity in patients with CD and to explore the contribution of motor and sensory components to ST mechanisms. To this purpose, we studied 15 CD patients with clinically effective ST, 17 without ST, and 14 healthy controls (HCs) who mimicked the ST. We used electroencephalographic (EEG) recordings and electromyography (EMG) data from bilateral sternocleidomastoid (SCM) muscles. We compared ST-related EEG spectral changes from sensorimotor and posterior parietal areas and EMG power changes between groups. To better understand the contribution of motor and sensory components to ST, we tested EEG and EMG correlates of three different conditions mimicking ST, the first without skin touch ("no touch" condition), the second without voluntary movements ("passive" condition), and finally without arm movements ("examiner touch" condition). Results showed ST-related alpha desynchronization in the sensorimotor cortex and theta desynchronization in the sensorimotor and posterior parietal cortex. Both spectral changes were more significant during maneuver execution in CD patients with ST than in CD patients without ST and HCs who mimicked the ST. Differently, the "no touch", "passive", or "examiner touch" conditions did not show significant differences in EEG or EMG changes determined by ST execution/mimicking between CD patients with or without ST. A higher desynchronization within alpha and theta bands in the sensorimotor and posterior parietal areas correlated with a more significant activity decrease in the contralateral SCM muscle, Findings from this study suggest that ST-related changes in the activity of sensorimotor and posterior parietal areas may restore dystonic posture and that both motor and sensory components contribute to the ST effect.

Investigating the Effects of a Focal Muscle Vibration Protocol on Sensorimotor Integration in Healthy Subjects.

Background: The ability to perceive two tactile stimuli as asynchronous can be measured using the somatosensory temporal discrimination threshold (STDT). In healthy humans, the execution of a voluntary movement determines an increase in STDT values, while the integration of STDT and movement execution is abnormal in patients with basal ganglia disorders. Sensorimotor integration can be modulated using focal muscle vibration (fMV), a neurophysiological approach that selectively activates proprioceptive afferents from the vibrated muscle. Method: In this study, we investigated whether fMV was able to modulate STDT or STDT-movement integration in healthy subjects by measuring them before, during and after fMV applied over the first dorsalis interosseous, abductor pollicis brevis and flexor radialis carpi muscles. Results: The results showed that fMV modulated STDT-movement integration only when applied over the first dorsalis interosseous, namely, the muscle performing the motor task involved in STDT-movement integration. These changes occurred during and up to 10 min after fMV. Differently, fMV did not influence STDT at rest. We suggest that that fMV interferes with the STDT-movement task processing, possibly disrupting the physiological processing of sensory information. Conclusions: This study showed that FMV is able to modulate STDT-movement integration when applied over the muscle involved in the motor task. This result provides further information on the mechanisms underlying fMV, and has potential future implications in basal ganglia disorders characterized by altered sensorimotor integration.

White and gray matter alterations in de novo PD patients: which matter most?

OBJECTIVES: This paper aimed to identify white matter (WM) and gray matter (GM) abnormalities in a sample of early PD patients, and their correlations with motor and non-motor symptom severity. METHODS: We enrolled 62 de novo PD patients and 31 healthy subjects. Disease severity and non-motor symptom burden were assessed by the Unified Parkinson's Disease Rating Scale part III and the Non-Motor Symptoms Scale, respectively. Cognitive performance was assessed using Montreal Cognitive Assessment and Frontal Assessment Battery. All subjects underwent a 3-Tesla MRI protocol. MRI analyses included tract-based spatial statistics, cortical thickness, and subcortical and cerebellar volumetry. RESULTS: In comparison to control subjects, PD patients exhibited lower fractional anisotropy and higher mean, axial, and radial diffusivity in most WM bundles, including corticospinal tracts, the internal and external capsule, the anterior and posterior thalamic radiations, the genu and body of the corpus callosum, cerebellar peduncles, and superior and inferior longitudinal and fronto-occipital fasciculi. Correlations between Montreal Cognitive Assessment scores and fractional anisotropy values in the right posterior thalamic radiation, left superior corona radiata, right inferior-fronto-occipital fasciculus, left inferior longitudinal fasciculus, bilateral anterior thalamic radiations, and bilateral superior longitudinal fasciculi were found. Smaller cerebellar volumes in early PD patients in the left and right crus I were also found. No GM changes were present in subcortical or cortical regions. CONCLUSION: The combined evaluation of WM and GM in the same patient sample demonstrates that WM microstructural abnormalities precede GM structural changes in early PD patients.

Pathophysiological mechanisms of oromandibular dystonia.

Oromandibular dystonia (OMD) is a rare form of focal idiopathic dystonia. OMD was clinically identified at the beginning of the 20th century, and the main clinical features have been progressively described over the years. However, OMD has several peculiarities that still remain unexplained, including the high rate of oral trauma, which is often related to the onset of motor symptoms. The purpose of this paper was to formulate a hypothesis regarding the pathophysiology of OMD, starting from the neuroanatomical basis of the masticatory and facial systems and highlighting the features that differentiate this condition from other forms of focal idiopathic dystonia. We provide a brief review of the clinical and etiological features of OMD as well as neurophysiological and neuroimaging findings obtained from studies in patients with OMD. We discuss possible pathophysiological mechanisms underlying OMD and suggest that abnormalities in sensory input processing may play a prominent role in OMD pathophysiology, possibly triggering a cascade of events that results in sensorimotor cortex network dysfunction. Finally, we identify open questions that future studies should address, including the effect of abnormal sensory input processing and oral trauma on the peculiar neurophysiological abnormalities observed in OMD.

State-dependent tDCS modulation of the somatomotor network: A MEG study.

OBJECTIVE: Transcranial direct current stimulation (tDCS) is a non-invasive technique widely used to investigate brain excitability and activity. However, the variability in both brain and behavioral responses to tDCS limits its application for clinical purposes. This study aims to shed light on state-dependency, a phenomenon that contributes to the variability of tDCS. METHODS: To this aim, we investigated changes in spectral activity and functional connectivity in somatomotor regions after Real and Sham tDCS using generalized additive mixed models (GAMMs), which allowed us to investigate how modulation depends on the initial state of the brain. RESULTS: Results showed that changes in spectral activity, but not connectivity, in the somatomotor regions depend on the initial state of the brain, confirming state-dependent effects. Specifically, we found a non-linear interaction between stimulation conditions (Real vs Sham) and initial state: a reduction of alpha and beta power was observed only in participants that had higher alpha and beta power before Real tDCS. CONCLUSIONS: This study highlights the importance of considering state-dependency to tDCS and shows how it can be taken into account with appropriate statistical models. SIGNIFICANCE: Our findings bear insight into tDCS mechanisms, potentially leading to discriminate between tDCS responders and non-responders.

Electroencephalographic hallmarks of Alzheimer's disease.

In the human brain, physiological aging is characterized by progressive neuronal loss, leading to disruption of synapses and to a degree of failure in neurotransmission and information flow. However, there is increasing evidence to support the notion that the aged brain has a remarkable level of resilience (i.s. ability to reorganize itself), with the aim of preserving its physiological activity. It is therefore of paramount interest to develop objective markers able to characterize the biological processes underlying brain aging in the intact human, and to distinguish them from brain degeneration associated to age-related neurological progressive diseases like Alzheimer's disease. EEG, alone and combined with transcranial magnetic stimulation (TMS-EEG), is particularly suited to this aim, due to the functional nature of the information provided, and thanks to the ease with which it can be integrated in ecological scenarios including behavioral tasks. In this review, we aimed to provide the reader with updated information about the role of modern methods of EEG and TMS-EEG analysis in the investigation of physiological brain aging and Alzheimer's disease. In particular, we focused on data about cortical connectivity obtained by using readouts such graph theory network brain organization and architecture, and transcranial evoked potentials (TEPs) during TMS-EEG. Overall, findings in the literature support an important potential contribution of such neurophysiological techniques to the understanding of the mechanisms underlying normal brain aging and the early (prodromal/pre-symptomatic) stages of dementia.

Brainstem Reflexes in Idiopathic Cervical Dystonia: Does Medullary Dysfunction Play a Role?

BACKGROUND: Neurophysiological markers in dystonia have so far not been sistematically applied in clinical practice due to limited reproducibility of results and low correlations with clinical findings. Exceptions might be represented by the blink reflex (BR), including its recovery cycle (BRRC) and the trigemino-cervical reflex (TCR) which, compared to other neurophysiological methods, have shown more consistent alterations in cervical dystonia (CD). However, a comparison between the two techniques, and their possible correlation with disease symptoms, have not been thoroughly investigated. OBJECTIVES: To assess the role of BR, BRCC and TCR in the pathophysiology of idiopathic cervical dystonia. METHODS: Fourteen patients and 14 age-matched healthy controls (HC) were recruited. Neurophysiological outcome measures included latency of R1 and R2 components of the BR, R2 amplitude, BRRC, latency and amplitude of P19/N31 complex of TCR. Clinical and demographic features of patients were also collected, including age at disease onset, disease duration, presence of tremor, sensory trick and pain. The Toronto Western Spasmodic Torticollis Rating Scale was used to characterize dystonia. RESULTS: Compared to HC, CD patients showed increased latency of the BR R2 and decreased suppression of the BRRC. They also showed increased latency of the P19 and decreased amplitude of P19/N31 complex of TCR. The latency of P19 component of TCR was positively correlated with disease duration. CONCLUSIONS: We propose that the increased latency of R2 and P19 observed here might be reflective of brainstem dysfunction, mediated either by local interneuronal excitability changes or by subtle structural damage.