A candidate projective neuron type of the cerebellar cortex: the synarmotic neuron.

Previous studies on the granular layer of the cerebellar cortex have revealed a wide distribution of different subpopulations of less-known large neuron types, called "non-traditional large neurons", which are distributed in three different zones of the granular layer. These neuron types are mainly involved in the formation of intrinsiccircuits inside the cerebellar cortex. A subpopulation of these neuron types is represented by the synarmotic neuron, which could play a projective role within the cerebellar circuitry. The synarmotic neuron cell body map within the internal zone of the granular layer or in the subjacent white substance. Furthermore, the axon crosses the granular layer and runs in the subcortical white substance, to reenter in an adjacent granular layer, associating two cortico-cerebellar regions of the same folium or of different folia, or could project to the intrinsic cerebellar nuclei. Therefore, along with the Purkinje neuron, the traditional projective neuron type of the cerebellar cortex, the synarmotic neuron is candidate to represent the second projective neuron type of the cerebellar cortex. Studies of chemical neuroanatomy evidenced a predominant inhibitory GABAergic nature of the synarmotic neuron, suggesting that it may mediate an inhibitory GABAergic output of cerebellar cortex within cortico-cortical interconnections or in projections towards intrinsic cerebellar nuclei. On this basis, the present minireview mainly focuses on the morphofunctional and neurochemical data of the synarmotic neuron, and explores its potential involvement in some forms of cerebellar ataxias.

Current Challenges in the Diagnosis of Progressive Neurocognitive Disorders: A Critical Review of the Literature and Recommendations for Primary and Secondary Care.

Screening for early symptoms of cognitive impairment enables timely interventions for patients and their families. Despite the advances in dementia diagnosis, the current nosography of neurocognitive disorders (NCDs) seems to overlook some clinical manifestations and predictors that could contribute to understanding the conversion from an asymptomatic stage to a very mild one, eventually leading to obvious disease. The present review examines different diagnostic approaches in view of neurophysiological and neuropsychological evidence of NCD progression, which may be subdivided into: (1) preclinical stage; (2) transitional stage; (3) prodromal or mild stage; (4) major NCD. The absence of univocal criteria and the adoption of ambiguous or narrow labels might complicate the diagnostic process. In particular, it should be noted that: (1) only neuropathological hallmarks characterize preclinical NCD; (2) transitional NCD must be assessed through proactive neuropsychological protocols; (3) prodromal/mild NCDs are based on cognitive functional indicators; (4) major NCD requires well-established tools to evaluate its severity stage; (5) insight should be accounted for by both patient and informants. Therefore, the examination of evolving epidemiological and clinical features occurring at each NCD stage may orient primary and secondary care, allowing for more targeted prevention, diagnosis, and/or treatment of both cognitive and functional impairment.

The Cerebellar Dopaminergic System.

In the central nervous system (CNS), dopamine (DA) is involved in motor and cognitive functions. Although the cerebellum is not been considered an elective dopaminergic region, studies attributed to it a critical role in dopamine deficit-related neurological and psychiatric disorders [e.g., Parkinson's disease (PD) and schizophrenia (SCZ)]. Data on the cerebellar dopaminergic neuronal system are still lacking. Nevertheless, biochemical studies detected in the mammalians cerebellum high dopamine levels, while chemical neuroanatomy studies revealed the presence of midbrain dopaminergic afferents to the cerebellum as well as wide distribution of the dopaminergic receptor subtypes (DRD1-DRD5). The present review summarizes the data on the cerebellar dopaminergic system including its involvement in associative and projective circuits. Furthermore, this study also briefly discusses the role of the cerebellar dopaminergic system in some neurologic and psychiatric disorders and suggests its potential involvement as a target in pharmacologic and non-pharmacologic treatments.

Rest tremor in Parkinson's disease: Body distribution and time of appearance.

OBJECTIVE: To assess body distribution and timing of appearance of rest tremor in Parkinson's disease. METHODS: Information was obtained by a computerized database containing historical information collected at the first visit and data collected during the subsequent follow-up visits. Information on rest tremor developed during the follow-up could be therefore obtained by our own observation in a proportion of patients. RESULTS: Among 289 patients, rest tremor was reported at disease onset in 65.4% of cases and detected at last follow-up examination in 74.4% of patients. Analysis of patients who did not report rest tremor at disease onset indicated that 26% of such patients (9% in the overall population) manifested rest tremor over the disease course. Rest tremor spread to new sites in 39% of patients who manifested rest tremor at disease onset. Regardless of tremor presentation at disease onset or during the follow-up, upper limb was the most frequent tremor localization. Over the follow-up, rest tremor developed faster in the upper limb than in other body sites. The risk of developing rest tremor during the follow-up was not affected by sex, side of motor symptom onset and site of tremor presentation. However, age of disease onset >63years was associated with an increased risk of rest tremor spread. CONCLUSIONS: This study provides new information about body distribution and timing of rest tremor appearance during the course of early stages of Parkinson's disease that may help clinicians in patients' counselling.

Laser-evoked potential habituation and central sensitization symptoms in childhood migraine.

OBJECTIVES: Few studies have addressed central sensitization symptoms and pain processing in childhood migraine. Our aims were to examine pain sensitivity and responses, including habituation, evoked by CO2 laser stimuli (laser-evoked potentials (LEPs)) in a cohort of children with migraine compared to non-migraine controls and to determine the correlation between LEP features and signs of central sensitization. METHODS: Thirty-five patients 8-15 years of age with migraines without aura were evaluated during the inter-critical phase and were compared to 17 controls. LEPs were analyzed, and their main features were correlated with clinical symptoms including allodynia and pericranial tenderness. RESULTS: The laser-evoked pain threshold was lower and the N2P2 vertex complex amplitude was higher in children with migraines. Furthermore, habituation of vertex waves of LEPs clearly showed a tendency toward progressive amplitude enhancement in the migraine group. Acute allodynia and inter-critical pericranial tenderness correlated with trigeminal LEP features, particularly with the abnormal habituation pattern. DISCUSSION: Abnormalities of pain processing and symptoms of central sensitization appear to be characteristics of children with migraine. Reduced habituation and progressive amplification of cortical responses to laser stimuli indicate an overactive nociceptive system at the onset of migraine, and this hyperactivity may subtend allodynia and pericranial tenderness. Future prospective trials may aid in the early identification of clinical phenotypes that display a tendency to develop into the chronic form of migraine, warranting a timely therapeutic approach.

Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state.

AIMS: Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient visual, acoustic, somatosensory electric non-nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation. METHODS: Five Vegetative State (VS), 4 Minimally Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 s. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2) vertex complex in the 500 ms post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R) and Coma Recovery Scale (CRS-R) for clinical evaluation of pain perception and consciousness impairment. RESULTS: The laser evoked potentials (LEPs) were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. DISCUSSION: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the degree of cognitive and motor behavior recovery. This underlines the importance of considering the potential experience of pain also in patients in vegetative state and to appropriately assess a possible treatment also in those patients.

Sleep features and central sensitization symptoms in primary headache patients.

BACKGROUND: Association between sleep disorders and headache is largely known. The aim of the present study was to evaluate sleep quality and quantity in a large cohort of primary headache patients, in order to correlate these scores with symptoms of central sensitization as allodynia, pericranial tenderness and comorbidity with diffuse muscle-skeletal pain. METHODS: One thousand six hundreds and seventy primary headache out patients were submitted to the Medical Outcomes Study (MOS) within a clinical assessment, consisting of evaluation of frequency of headache, pericranial tenderness, allodynia and coexistence of fibromyalgia syndrome (FM). RESULTS: Ten groups of primary headache patients were individuated, including patients with episodic and chronic migraine and tension type headache, mixed forms, cluster headache and other trigeminal autonomic cephalalgias. Duration but not sleep disturbances score was correlated with symptoms of central sensitization as allodynia and pericranial tenderness in primary headache patients. The association among allodynia, pericranial tenderness and short sleep characterized chronic migraine more than any other primary headache form. Patients presenting with FM comorbidity suffered from sleep disturbances in addition to reduction of sleep duration. CONCLUSION: Self reported duration of sleep seems a useful index to be correlated with allodynia, pericranial tenderness and chronic headache as a therapeutic target to be assessed in forthcoming studies aiming to prevent central sensitization symptoms development.

Disease modeling in functional movement disorders.

INTRODUCTION: The mechanisms underlying functional movement disorders are poorly known. We examined whether experience of a movement disorder model in the family and/or the friendships contributes to functional movement disorders. METHODS: The hypothesis was tested in a case-control study including 33 patients with functional movement disorders and 66 age- and sex-matched patients with organic movement disorders and using a conditional logistic multivariable analysis (adjusted by age, education, disease duration, chronic medical illnesses and clinical phenotype). RESULTS: Case-control comparison yielded a significant association between functional movement disorders and exposure to phenotypically congruent movement disorder models (Odds ratio, 3.9, p = 0.01), mainly when disease model came from friendships (Odds ratio, 5.9, p = 0.04). By contrast no association was found between functional movement disorders and phenotypically different neurological or non neurological disease models. A significant inverse relationship between exposure to a phenotypically concordant movement disorder model and age of disease onset was also observed. CONCLUSIONS: These findings support disease modeling as a factor contributing to the phenomenology of functional movement disorders.

Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial.

OBJECTIVE: To assess the efficacy, safety and tolerability of sodium valproate (800mg/die) compared with placebo in medication-overuse headache patients with a history of migraine without aura. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled study enrolled medication-overuse headache patients for a 3-month treatment period with sodium valproate (800mg/day) or placebo after a 6 day outpatient detoxification regimen, followed by a 3-month follow-up. Primary outcome was defined by the proportion of patients achieving ≥50% reduction in the number of days with headache per month (responders) from the baseline to the last 4 weeks of the 3-month treatment. Multivariate logistic regression models were used on the primary endpoint, adjusting for age, sex, disease duration, comorbidity and surgery. The last-observation-carried-forward method was used to adjust for missing values. RESULTS: Nine sites enrolled 130 patients and, after a 6-day detoxification phase, randomized 88 eligible patients. The 3-month responder rate was higher in the sodium valproate (45.0%) than in the placebo arm (23.8%) with an absolute difference of about 20% (p=0.0431). Sodium valproate had safety and tolerability profiles comparable to placebo. CONCLUSIONS: The present study supports the efficacy and safety of sodium valproate in the treatment of medication overuse headache with history of migraine after detoxification.

Age-related vascular differences among patients suffering from multiple sclerosis.

The aim of our study was to analyze morphological and functional aspects of cerebral veins by means of ecocolor-Doppler in young (i.e., ≤ 30 years old) and older (i.e., >30 years old) patients suffering from multiple sclerosis. 552 multiple sclerosis patients were evaluated by means of a dedicated Echo-Color-Doppler support (MyLab Vinco echocolor Doppler System, Esaote), in both supine and sitting positions. 458 (83%) showed alterations in their morphological and functional structures of cerebral veins and were divided in two different groups: 1) ≤ 30 (110 patients) and 2) >30 years old (348 patients). Young patients showed a statistically significant higher number of both hemodynamically (44% vs. 35%, p<0.01) and non-hemodynamically (51% vs. 45%, p<0.05) significant stenosis in the internal jugular veins as compared to older patients. A lower percentage of young patients showed blocked outflow in the cervical veins (50% vs. 65%, p<0.01) as compared to older ones. Patients >30 years old outlined a significantly higher disability degree (Expanded Disability Status Scale score: 5 vs. 3, p<0.01) as well as higher disease duration (12 vs. 5 months, p<0.01) than younger. No differences could be outlined about multiple sclerosis clinical form of the disease. It was evidenced that young and adult groups are different kind of patients, the former showing much more cerebral veins stenosis and blocked flow in internal jugular veins and vertebral veins than the latter. Duration of disease could explain such differences: the higher the diseases duration, the higher the degree of vascular alterations and, therefore, the disability degree. This could be due to the complex venous hemodynamic impairments induced by alterations in vascular walls: the blocked or difficult blood flow through stenosis could increase the hydrostatic pressure in the skull and this could induce damages to cerebral cells leading to the genesis of more advanced morphological abnormalities. Furthermore, the vessels' alterations could impair venous endothelial functions which could turn in a possible alteration of the controls of cerebral vein return which could worsen the cerebral vascular outflow. It may be possible that early clinical, pharmacological and/or invasive vascular interventions could exert a possible role in the natural history of multiple sclerosis. Nevertheless, further trials are needed in order to confirm such considerations.

Update on laser-evoked potential findings in fibromyalgia patients in light of clinical and skin biopsy features.

In fibromyalgia (FM), reduced habituation of laser-evoked potentials (LEPs) suggests a dysfunction of pain processing at a central level. In this study, we aimed to further examine the nociceptive pathways at the peripheral to the central level in a large group of FM patients by means of LEPs and skin biopsy, in light of healthy controls findings and main clinical features. One hundred and ninety-nine FM patients and 109 age- and sex-matched controls were submitted to LEPs by the dorsum of the right hand and the skin over the right chest and knee tender point stimulation. Skin biopsy was performed in 21 randomly selected FM patients and 60 age- and sex-matched controls. The mean N2-P2 amplitude was reduced in the whole FM group, with normal or even increased values in patients with migraine as comorbidity and reduced values in other patients including those presenting with distal sensory deficits. All patients had reduced N2-P2 habituation in respect to controls. In the FM group, LEPs habituation was correlated with pain at tender points and bad quality of life. Epidermal fiber density was significantly reduced in FM patients versus controls, and correlated with N2-P2 amplitude by the hand and chest tender-point stimulation. Dysfunction in the nociceptive system at both the central and peripheral levels may concur to explain phenotypical eterogeneity and clinical symptom complexity in fibromyalgia.

Impaired cognitive functions in adult-onset primary cranial cervical dystonia.

BACKGROUND: Adult-onset primary dystonia is thought to be a purely motor disorder. Nevertheless, several studies provided evidence that sensory and psychiatric disturbances may contribute to the clinical spectrum of of dystonia, whereas evidence supporting cognitive impairment is still limited. METHODS: A set of neuropsychological tests was administered to non depressed, non demented patients with cranial-cervical dystonia and healthy control subjects. The test battery included n-Back Task, Wechsler Memory Scale, Trail Making Test version A and B, and Wisconsin Card Sorting Test. RESULTS: As compared with healthy control subjects of similar age, sex and socio-economic status, patients with cranial-cervical dystonia showed deficit on working memory functions revealed by n-Back task, impairment of mental control and visual reproduction subtests of Wechsler memory scale, deficit on information processing speed and set-shifting capacity revealed by Trail Making Test A and B. CONCLUSION: Patients with cranial-cervical dystonia may have impairment in specific cognitive domains relative to working memory, processing speed, visual motor ability and short term memory. Probably, these deficits are not dependent on the clinical expression of dystonia but might rather reflect the cortical and subcortical changes highlighted by functional and VBM imaging studies in patients with different forms of dystonia.

Pain in prolonged disorders of consciousness: laser evoked potentials findings in patients with vegetative and minimally conscious states.

INTRODUCTION: Pain perception is currently an open question in patients suffering from prolonged disorders of consciousness. The aim of the present study was to examine nociceptive specific laser evoked responses (LEPs) in view of long-latency evoked potentials by non-painful electrical stimuli (SEPs) and auditory mismatch negativity (MM). METHODS: Three vegetative state (VS), four minimal Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, stimulating the dorsum of the right hand by noxious laser and innocuous electrical stimulus, according to normal controls subjective rating. An auditory paradigm for MM was also employed. RESULTS: The MM was present in all patients. The LEP vertex complex was recognizable in all cases, with a significant latency increase of both N2 and P2 which displayed changes of topographic representation. Late SEPs were absent in all patients except in one MCS case, who showed a significant N2 and P2 latency increase. DISCUSSION: The results may suggest that high relevant stimuli may be processed even in patients with severe brain damage. Larger series and multimodal approaches may contribute to confirm that cortical arousal toward pain salience may be a primary function for life persistence.

Virtual visual effect of hospital waiting room on pain modulation in healthy subjects and patients with chronic migraine.

Environmental context has an important impact on health and well being. We aimed to test the effects of a visual distraction induced by classical hospital waiting room (RH) versus an ideal room with a sea view (IH), both represented in virtual reality (VR), on subjective sensation and cortical responses induced by painful laser stimuli (LEPs) in healthy volunteers and patients with chronic migraine (CM). Sixteen CM and 16 controls underwent 62 channels LEPs from the right hand, during a fully immersive VR experience, where two types of waiting rooms were simulated. The RH simulated a classical hospital waiting room while the IH represented a room with sea viewing. CM patients showed a reduction of laser pain rating and vertex LEPs during the IH vision. The sLORETA analysis confirmed that in CM patients the two VR simulations induced a different modulation of bilateral parietal cortical areas (precuneus and superior parietal lobe), and superior frontal and cingulate girus, in respect to controls. The architectural context may interfere with pain perception, depending upon the status of subject. Many variables may change patients' outcome and support the use of VR technology to test the best conditions for their management.

ß-Site amyloid precursor protein-cleaving enzyme 1 activity is related to cerebrospinal fluid concentrations of sortilin-related receptor with A-type repeats, soluble amyloid precursor protein, and tau.

BACKGROUND: ß-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity determines the rate of APP cleavage and is therefore the main driver of amyloid ß production, which is a pathological hallmark of Alzheimer's disease (AD). METHODS: The present study explored the correlation between BACE1 activity and cerebrospinal fluid (CSF) markers of APP metabolism and axonal degeneration in 63 patients with mild AD and 12 healthy control subjects. RESULTS: In the AD group, positive correlations between BACE1 activity and soluble APP ß, the APP sorting receptor sortilin-related receptor with A-type repeats (also known as SorLA or LR11), and tau were detected. BACE1 activity was not associated with amyloid ß1-42 or soluble APP α concentrations in the AD group, and no associations between BACE1 activity and any of the protein concentrations were found in the control group. CONCLUSION: Our results confirm the relevance of BACE1 and sortilin-related receptor with A-type repeats within the amyloid cascade and also provide a further piece of evidence for the link between amyloid and tau pathology in AD.

Tremor in primary adult-onset dystonia: prevalence and associated clinical features.

OBJECTIVE: To investigate the frequency and the main clinical features of tremor in primary adult-onset dystonia (PAOD). METHODS: This cross-sectional study was conducted on 429 patients with PAOD from eight Italian movement disorder centres. RESULTS: Of the 429 dystonic patients, 72 (16.7%) had tremor. Although sex and age at dystonia onset were similar in dystonic patients who had tremor and those who did not, patients who had tremor were affected more often by focal cervical dystonia and less often by focal blepharospasm. Dystonia had a greater tendency to spread in patients with tremor. According to the Movement Disorder Society Consensus Statement, tremor was classified as dystonic tremor (DT) in 43 patients and tremor associated with dystonia (TAWD) in 23 patients. Six patients had both types of tremor. Taking into account potential confounding by age at onset and body distribution of the corresponding dystonia type, all the clinical features in patients with DT and in those with TAWD were comparable except the tendency of dystonia to spread, which was greater in patients with DT. CONCLUSIONS: Tremor is a relatively common feature occurring in about 17% of patients with primary late-onset dystonia. The association between tremor and dystonia spread suggests that this form of tremor may be a dystonic manifestation. Similarities in phenotypic features of DT and TAWD predominated over differences, suggesting that the two forms of tremor may be manifestations of the same disease. Differences in gender and body distribution of tremor between patients with dystonia and tremor and those of patients with essential tremor also suggest that tremor in dystonia and essential tremor are different entities.

Comparison of tolerability and efficacy of a combination of paracetamol + caffeine and sumatriptan in the treatment of migraine attack: a randomized, double-blind, double-dummy, cross-over study.

In this study, we compared the efficacy and tolerability of the combination of paracetamol 1,000 mg + caffeine 130 mg (PCF) with sumatriptan 50 mg (SUM) in migraine attacks. This was a multi-center randomized double-blind, double-dummy, cross-over controlled trial. The efficacy was assessed by the sum of pain intensity differences, the curve of mean pain intensity, the number of pain free at 2 h, and the total pain relief. Tolerability was assessed by recording adverse events within 4 h after drug assumption and evaluating the global judgement of patients. The comparison of these parameters did not show differences between the two drugs which resulted absolutely overlapping in pain relief and patients evaluation. In conclusion, we confirm the efficacy and safety of PCF such as SUM in the treatment of migraine attacks.