The efficacy of non-invasive brain stimulation in the treatment of children and adolescents with Anorexia Nervosa: study protocol of a randomized, double blind, placebo-controlled trial.

BACKGROUND: Current psychological and pharmacological treatments for Anorexia Nervosa (AN) provide only moderate effective support, and there is an urgent need for research to improve therapies, especially in developing age. Non-invasive brain stimulation has suggested to have the potential to reducing AN symptomatology, via targeting brain alterations, such as hyperactivity of right prefrontal cortex (PFC). We suppose that transcranial direct current stimulation (tDCS) to the PFC may be effective in children and adolescents with AN. METHODS: We will conduct a randomized, double blind, add-on, placebo-controlled trial to investigate the efficacy of tDCS treatment on clinical improvement. We will also investigate brain mechanisms and biomarkers changes acting in AN after tDCS treatment. Eighty children or adolescent with AN (age range 10-18 years) will undergo treatment-as-usual including psychiatric, nutritional and psychological support, plus tDCS treatment (active or sham) to PFC (F3 anode/F4 cathode), for six weeks, delivered three times a week. Psychological, neurophysiological and physiological measures will be collected at baseline and at the end of treatment. Participants will be followed-up one, three, six months and one year after the end of treatment. Psychological measures will include parent- and self-report questionnaires on AN symptomatology and other psychopathological symptoms. Neurophysiological measures will include transcranial magnetic stimulation (TMS) with electroencephalography and paired pulse TMS and repetitive TMS to investigate changes in PFC connectivity, reactivity and plasticity after treatment. Physiological measures will include changes in the functioning of the endogenous stress response system, body mass index (BMI) and nutritional state. DISCUSSION: We expect that tDCS treatment to improve clinical outcome by reducing the symptoms of AN assessed as changes in Eating Disorder Risk composite score of the Eating Disorder Inventory-3. We also expect that at baseline there will be differences between the right and left hemisphere in some electrophysiological measures and that such differences will be reduced after tDCS treatment. Finally, we expect a reduction of endogenous stress response and an improvement in BMI and nutritional status after tDCS treatment. This project would provide scientific foundation for new treatment perspectives in AN in developmental age, as well as insight into brain mechanisms acting in AN and its recovery. Trial registration The study was registered at ClinicalTrials.gov (ID: NCT05674266) and ethical approval for the study was granted by the local research ethics committee (process number 763_OPBG_2014).

Intraoperative Neuromonitoring for Thyroid Surgery in Children and Adolescents: A Single Center Experience.

Intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN) has been shown in adults to minimize nerve palsy after thyroid surgery, but only few studies on its efficacy in a pediatric population have been reported. We conducted a retrospective study on patients operated for thyroid lesions from 2016 to 2022. The analyzed population was divided in two groups: patients treated from 2016 to 2020, when the identification of the RLN was performed without IONM (Group A); and patients treated since 2021, when IONM was implemented in every surgical procedure on the thyroid (Group B). Intraoperative Neurophysiological Monitoring was performed by using corticobulbar motor-evoked potentials and continuous electromyography. Twentyfive children underwent thyroid resection, 19 (76%) of which due to thyroid carcinoma. Each patient's recurrent nerve was identified; IONM was used in 13 patients. In Group A, one temporary nerve palsy was identified postoperatively (8.3%), while in group B one nerve dysfunction occurred (7.7%). No statistically significant difference was found between the two groups in terms of post-operative RLN palsy. No surgical complication due to the use of IONM was reported. In children and teenagers, intraoperative neuromonitoring of the recurrent laryngeal nerve is a safe and accurate method, minimizing the risk of nerve damage.

Intraoperative Neuromonitoring for Pediatric Pelvic Tumors.

Background: Tumors of the pre-sacral and sacral spaces are a rare occurrence in children. Total tumor excision is required due to the significant risk of relapse in the event of partial surgery, but the surgical procedure may lead to postoperative problems such as urinary, sexual, and anorectal dysfunctions. Intraoperative neuromonitoring (IONM) has gained popularity in recent years as a strategy for preventing the onset of neurologic impairments by combining several neurophysiological techniques. The aim of our study is to describe the experience of Bambino Gesù Children's Hospital in the use of IONM in pediatric pelvic surgery. Materials and Methods: The data of patients treated for pelvic malignancies at Bambino Gesù Children's Hospital from 2015 to 2019 were retrospectively collected. All patients were assessed from a neurologic and neuro-urologic point of view at different time-points (before and immediately after surgery, after 6 months, and 1-year follow-up). They were all monitored during a surgical procedure using multimodal IONM including transcranial motor evoked potentials (TcMEP), triggered-EMG (t-EMG), pudendal somatosensory evoked potentials (PSSEP), and bulbocavernosus reflex (BCR). Results: During the study period, ten children underwent pelvic tumor removal at our Institution. In all cases, intraoperative neurophysiological recordings were stable and feasible. The preservation of neurophysiological response at the same intensity during surgical procedures correlated with no new deficits for all neurophysiological techniques. Discussion: Although the impact of the IONM on surgical strategies and clinical follow-up is unknown, this preliminary experience suggests that the appropriate use of several neurophysiological techniques can influence both the radicality of pelvic tumor removal and the neurological and urological outcome at clinical follow-up. Finally, because of the highly complex anatomy and inter-individual variances, this is especially useful in this type of surgery.

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography.

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics.

Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease: A Randomized Clinical Trial.

Importance: Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD). Objective: To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD. Design, Setting, and Participants: This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019. Interventions: A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47). Main Outcomes and Measures: The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography. Results: Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group. Conclusions and Relevance: In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living. Trial Registration: ClinicalTrials.gov Identifier: NCT03250741.

Intraventricular Ectopic Cerebellum.

BACKGROUND: Cerebellar ectopy is a rare finding, with few cases previously reported. Intraventricular localized cerebellar ectopy was described in only 1 case within the fourth ventricle. CASE DESCRIPTION: A 9-year-old girl suffered for 2 years from bilateral frontoparietal headaches, sometimes accompanied by vomiting and photophobia. Magnetic resonance imaging demonstrated an oval-shaped lesion within the left lateral ventricle, characterized by well-defined margins without a clear cleavage plane from the adjacent choroid plexus. The mass presented an intermediate signal on T1- and T2-weighted sequences, similar to gray matter, and reduced ADC values on ADC maps compared with white matter, with no enhancement after gadolinium-based contrast injection. After resection, macroscopic examination revealed an organoid structure with leptomeningeal lining and a clear-cut cortex and white matter components. Histology demonstrated normal cerebellum with a double-layered cortex and normal underlying white matter. The cerebellar ectopy was focally covered by bundles of capillary vascular structures covered by a monostratified ependymal cell lining, consistent with choroid plexus. CONCLUSIONS: We describe, for the first time to our knowledge, the case of a child with ectopic cerebellar tissue harboring the supratentorial ventricular system. Plausible etiologic mechanism consists in the herniation of the cerebellar germinal tissue into the ventricular system through the ependyma, allowing cell migration to the supratentorial compartment, followed by maturation into the normal cerebellum.

Improving visuo-motor learning with cerebellar theta burst stimulation: Behavioral and neurophysiological evidence.

The cerebellum is strongly implicated in learning new motor skills. Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation, can be used to influence cerebellar activity. Our aim was to explore the potential of cerebellar TBS in modulating visuo-motor adaptation, a form of motor learning, in young healthy subjects. Cerebellar TBS was applied immediately before the learning phase of a visuo-motor adaptation task (VAT), in two different experiments. Firstly, we evaluated the behavioral effects of continuous (cTBS), intermittent (iTBS) or sham TBS on the learning, re-adaptation and de-adaptation phases of VAT. Subsequently, we investigated the changes induced by iTBS or sham TBS on motor cortical activity related to each phase of VAT, as measured by concomitant TMS/EEG recordings. We found that cerebellar TBS induced a robust bidirectional modulation of the VAT performance. More specifically, cerebellar iTBS accelerated visuo-motor adaptation, by speeding up error reduction in response to a novel perturbation. This gain of function was still maintained when the novel acquired motor plan was tested during a subsequent phase of re-adaptation. On the other hand, cerebellar cTBS induced the opposite effect, slowing the rate of error reduction in both learning and re-adaptation phases. Additionally, TMS/EEG recordings showed that cerebellar iTBS induced specific changes of cortical activity in the interconnected motor networks. The improved performance was accompanied by an increase of TMS-evoked cortical activity and a generalized desynchronization of TMS-evoked cortical oscillations. Taken together, our behavioral and neurophysiological findings provide the first-time multimodal evidence of the potential efficacy of cerebellar TBS in improving motor learning, by promoting successful cerebellar-cortical reorganization.

Extended release levodopa at bedtime as a treatment for nocturiain Parkinson's disease: An open label study.

BACKGROUND: Bladder dysfunction may cause disabling symptoms in Parkinson's disease (PD) patients. The majority patients' experience symptoms as urinary urgency and nocturia suggest overactive bladder. This seems to be due to an altered brain-bladder relationship because of alteration in fronto-basal ganglia D1-dopaminergic circuit that normally suppresses micturition-reflex. Previous studies demonstrated beneficial effect of D1/D2 dopamine-receptors chronic-stimulation on detrusor overactivity of PD-patients.The present study was aimed to evaluate possible effect of extended-release (ER) Levodopa administered at bed-time on both nocturia and nocturia-related quality-of-life (NQoL) in PD-patients. METHODS: 106 PD-patients (Hoehn and Yahr>1 and < 4, mean age 66 years, 59 females and 47 males) were enrolled by 7 Movement Disorders out-patients clinics. Patients undergo to International Prostatic Symptoms Scale-IPSS, including 1-item about nocturia (item 7), and to Nocturia Quality of Life-NQoL questionnaire, at baseline and after two-months of Extended-Release L-dopa (L-dopa/carbidopa or L-dopa benserazide) treatment at bed-time. RESULTS: Statistical analysis showed significant improvement on both total IPSS, item 7and NQoL scores following two-months ER L-dopa-treatment. ΔIPSS score inversely correlated with disease duration. CONCLUSIONS: This results support previous evidence of pathophysiological involvement of dopaminergic transmission on bladder dysfunction in PD.

Neurophysiological and clinical effects of blindfolded balance training (BBT) in Parkinson's disease patients: a preliminary study.

BACKGROUND: Recent evidence supports the hypothesis that rehabilitative strategies based on sensorimotor stimulation in the neurorehabilitation of Parkinson's disease (PD) may be useful to improve gait in PD patients. AIM: We supposed that sensorimotor stimulation produces modulation of anticipatory postural adjustments (APAs) arising from the supplementary motor area (SMA). We aimed to investigate the clinical and neurophysiological effects of a blindfolded balance training (BBT). DESIGN: Randomized controlled trial. SETTING: Italian hospital. POPULATION: Sixteen PD patients. METHODS: The patients were randomized in two groups, one group treated with two-weeks BBT and one group treated with two-weeks of physical therapy (PT). We assessed gait parameters (swing, stance, double stance phase of cycle gait) and neurophysiological measurement (functional connectivity between SMA and motor area M1) before and after treatments. RESULTS: We found a decrease of stance and double stance phase and increase of swing phase respect to gait cycle, in BBT group compared to PT group, paralleled by a selective modulation in functional connectivity between M1 and SMA for BBT group. CONCLUSIONS: Our findings support that BBT represents a complementary rehabilitative strategy, based on visual deprivation and proprioceptive perturbation in recovery of gait in PD patients, in short time window, likely involving vestibular system and its connections with motor areas. CLINICAL REHABILITATION IMPACT: The use of vestibular system stimulation, involving SMA-M1 circuits, may be useful to improve gait control in PD patients.

Effect of Cerebellar Stimulation on Gait and Balance Recovery in Patients With Hemiparetic Stroke: A Randomized Clinical Trial.

Importance: Gait and balance impairment is associated with poorer functional recovery after stroke. The cerebellum is known to be strongly implicated in the functional reorganization of motor networks in patients with stroke, especially for gait and balance functions. Objective: To determine whether cerebellar intermittent θ-burst stimulation (CRB-iTBS) can improve balance and gait functions in patients with hemiparesis due to stroke. Design, Setting, Participants: This randomized, double-blind, sham-controlled phase IIa trial investigated efficacy and safety of a 3-week treatment of CRB-iTBS coupled with physiotherapy in promoting gait and balance recovery in patients with stroke. Thirty-six patients with consecutive ischemic chronic stroke in the territory of the contralateral middle cerebral artery with hemiparesis were recruited from a neuro-rehabilitation hospital. Participants were screened and enrolled from March 2013 to June 2017. Intention-to-treat analysis was performed. Interventions: Patients were randomly assigned to treatment with CRB-iTBS or sham iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side immediately before physiotherapy daily during 3 weeks. Main Outcomes and Measures: The primary outcome was the between-group difference in change from baseline in the Berg Balance Scale. Secondary exploratory measures included the between-group difference in change from baseline in Fugl-Meyer Assessment scale, Barthel Index, and locomotion assessment with gait analysis and cortical activity measured by transcranial magnetic stimulation in combination with electroencephalogram. Results: A total of 34 patients (mean [SD] age, 64 [11.3] years; 13 women [38.2%]) completed the study. Patients treated with CRB-iTBS, but not with sham iTBS, showed an improvement of gait and balance functions, as revealed by a pronounced increase in the mean (SE) Berg Balance Scale score (baseline: 34.5 [3.4]; 3 weeks after treatment: 43.4 [2.6]; 3 weeks after the end of treatment: 47.5 [1.8]; P < .001). No overall treatment-associated differences were noted in the Fugl-Meyer Assessment (mean [SE], baseline: 163.8 [6.8]; 3 weeks after treatment: 171.1 [7.2]; 3 weeks after the end of treatment: 173.5 [6.9]; P > .05) and Barthel Index scores (mean [SE], baseline: 71.1 [4.92]; 3 weeks after treatment: 88.8 [2.1]; 3 weeks after the end of treatment: 92.2 [2.4]; P > .05). Patients treated with CRB-iTBS, but not sham iTBS, showed a reduction of step width at the gait analysis (mean [SE], baseline: 16.8 [4.8] cm; 3 weeks after treatment: 14.3 [6.2] cm; P < .05) and an increase of neural activity over the posterior parietal cortex. Conclusions and Relevance: Cerebellar intermittent θ-burst stimulation promotes gait and balance recovery in patients with stroke by acting on cerebello-cortical plasticity. These results are important to increase the level of independent walking and reduce the risk of falling. Trial Registration: ClinicalTrials.gov Identifier: NCT03456362.

Transcranial magnetic stimulation predicts cognitive decline in patients with Alzheimer's disease.

OBJECTIVE: To determine the ability of transcranial magnetic stimulation (TMS) in detecting synaptic impairment in patients with Alzheimer's disease (AD) and predicting cognitive decline since the early phases of the disease. METHODS: We used TMS-based parameters to evaluate long-term potentiation (LTP)-like cortical plasticity and cholinergic activity as measured by short afferent inhibition (SAI) in 60 newly diagnosed patients with AD and 30 healthy age-matched subjects (HS). Receiver operating characteristic (ROC) curves were used to assess TMS ability in discriminating patients with AD from HS. Regression analyses examined the association between TMS-based parameters and cognitive decline. Multivariable regression model revealed the best parameters able to predict disease progression. RESULTS: Area under the ROC curve was 0.90 for LTP-like cortical plasticity, indicating an excellent accuracy of this parameter in detecting AD pathology. In contrast, area under the curve was only 0.64 for SAI, indicating a poor diagnostic accuracy. Notably, LTP-like cortical plasticity was a significant predictor of disease progression (p=0.02), while no other neurophysiological, neuropsychological and demographic parameters were associated with cognitive decline. Multivariable analysis then promoted LTP-like cortical plasticity as the best significant predictor of cognitive decline (p=0.01). Finally, LTP-like cortical plasticity was found to be strongly associated with the probability of rapid cognitive decline (delta Mini-Mental State Examination score ≤-4 points at 18 months) (p=0.04); patients with AD with lower LTP-like cortical plasticity values showed faster disease progression. CONCLUSIONS: TMS-based assessment of LTP-like cortical plasticity could be a viable biomarker to assess synaptic impairment and predict subsequent cognitive decline progression in patients with ADs.

Impaired Spike Timing Dependent Cortico-Cortical Plasticity in Alzheimer's Disease Patients.

BACKGROUND: Mechanisms of cortical plasticity have been recently investigated in Alzheimer's disease (AD) patients with transcranial magnetic stimulation protocols showing a clear impairment of long-term potentiation (LTP) cortical-like plasticity mechanisms. OBJECTIVE: We aimed to investigate mechanisms of cortico-cortical spike-timing dependent plasticity (STDP) in AD patients investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1). METHODS: We used a cortico-cortical paired associative stimulation (cc-PAS) protocol to repeatedly activate the connection between PPC and M1 of the left-dominant hemisphere in a sample of fifteen AD patients and ten age-matched healthy subjects. PPC transcranial magnetic stimulation preceded (ccPAS +5) or followed M1 stimulation (ccPAS - 5) by 5 ms. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity. RESULTS: In healthy subjects, ccPAS - 5 protocol induced the expected long-lasting increase of MEP amplitude compatible with LTP-like cortical plasticity while PAS +5 protocol induced the opposite effect. AD patients did not show any significant modification of the amplitude of MEP after both ccPAS protocols. CONCLUSIONS: Our study shows that in AD patients the time-locked activation of human cortico-cortical connections is not able to form STDP, reflecting an impairment of a multi-factor plasticity process.

Dysfunctional inhibitory control in Parkinson's disease patients with levodopa-induced dyskinesias.

INTRODUCTION: Chronic dopamine replacement therapies in Parkinson's disease can induce side effects, such as levodopa-induced dyskinesias and impulse control disorders. A dysfunction of inhibitory brain networks has been related to both disorders; however, there is no clear behavioral evidence supporting this hypothesis. We aimed to determine whether PD patients with levodopa-induced dyskinesias show features of increased impulsivity in parallel with altered motor inhibition. METHODS: Two matched samples of Parkinson's disease patients with (n = 14) or without (n = 14) levodopa-induced dyskinesias and a control group (n = 10) participated in the study. All groups were evaluated by the Barratt Impulsiveness Scale-11 to assess impulsivity traits. Furthermore, participants performed a stop signal task to evaluate reactive-motor inhibition and a Go/NoGo task to evaluate proactive-inhibitory control. PD patients were tested both in OFF and ON levodopa medication. RESULTS: Parkinson's disease patients with levodopa-induced dyskinesias showed higher impulsivity scores than PD patients without levodopa-induced dyskinesias. Dyskinetic patients presented also delayed stop signal reaction times indicating a worse performance in reactive inhibition. The slowness in inhibiting a motor command correlated with the impulsiveness scores. Furthermore, in the dyskinetic group, a positive correlation was found between stop reaction times and the severity of involuntary movements. Under the effect of levodopa, all patients were faster but dyskinetic patients were significantly less accurate in proactive inhibition. CONCLUSION: Inhibitory control is compromised in dyskinetic patients in parallel with increased impulsivity, revealing an impairment of motor and behavioral inhibitory control in Parkinson's disease patients with levodopa-induced dyskinesias.

Amyloid-Mediated Cholinergic Dysfunction in Motor Impairment Related to Alzheimer's Disease.

BACKGROUND: Although motor disturbances parallel the course of dementia, worsening both quality of life and social costs, the pathogenesis remains still unclear. OBJECTIVE: Through the combination of cerebrospinal fluid (CSF) biomarkers assessment and transcranial magnetic stimulation (TMS) protocols, here we provided a cross-sectional study to understand pathogenic mechanisms of Alzheimer's disease (AD)-related early motor disturbances. METHODS: The motor phenotype, as defined with Unified Parkinson's Disease Rating Scale (UPDRS) part 2-3, Rating Scale for Gait Evaluation in Cognitive Deterioration (RSEGCD) and Tinetti scale, together with CSF profile of amyloid-ß 42 (Aß42), total-tau, and phosphorylated-tau were determined in 37 AD patients and compared to 18 patients with vascular dementia (VaD). A TMS protocol of short afferent inhibition (SAI) was further applied on a subset of AD patients. Clinical, biochemical, and neurophysiological data were then compared and correlated in order to find significant associations. RESULTS: AD patients exhibited subtle locomotor impairment and slight extrapyramidal signs. Main motor features (UPDRS part 3, RSGECD, and Tinetti scale scores) correlate with Aß42 levels but not with t-tau and p-tau. AD patients also presented SAI impairment directly related to UPDRS part 3 score and Aß42 levels. Motor disturbances of VaD group did not differ statistically from AD and did not correlate with CSF biomarkers. CONCLUSIONS: The association of motor disturbances with low Aß42 CSF levels and individual SAI suggests that amyloid-mediated degeneration of cholinergic system may account for early AD-related motor impairment, providing interesting insights either for frailty stratification of patients or personalized therapies.

Osteopathic Manipulative Therapy Potentiates Motor Cortical Plasticity.

CONTEXT: Osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) is effective in managing pain caused by a variety of clinical conditions. Nevertheless, the physiologic mechanisms at the basis of the clinical improvement are poorly understood. OBJECTIVE: To investigate the effects of OMTh, muscle stretching, and soft touch interventions on motor cortical excitability through a rapid-rate paired associative stimulation (PAS) protocol. METHODS: In this crossover study, participants underwent OMTh, muscle stretching, and soft touch interventions. A rapid-rate PAS transcranial magnetic stimulation protocol was performed immediately after each intervention session, which consisted of 600 pairs of stimuli continuously delivered to the left primary motor cortex and to the right median nerve at a rate of 5 Hz for 2 minutes. The interstimulus intervals between the peripheral stimulus and the transcranial magnetic stimulation was set at 25 milliseconds. Before and after rapid-rate PAS (immediately after and 15 minutes after), changes in the amplitude of the motor evoked potentials were measured in the right abductor pollicis brevis and the right first dorsal interosseous. RESULTS: Of the potential 15 participants initially recruited, 12 fit the inclusion criteria. Two of the 12 participants were excluded from the final analysis because of excessive artifact movements. Rapid-rate PAS induced a more pronounced, longer-lasting increase in cortical excitability in the abductor pollicis brevis muscle in patients 15 minutes after the OMTh intervention than after the muscle stretching or sham interventions (P=.016). CONCLUSION: Results of the current study provide support for the effects of OMTh on cortical plasticity.

Dynamic reorganization of TMS-evoked activity in subcortical stroke patients.

Since early days after stroke, the brain undergoes a complex reorganization to allow compensatory mechanisms that promote functional recovery. However, these mechanisms are still poorly understood and there is urgent need to identify neurophysiological markers of functional recovery after stroke. Here we aimed to track longitudinally the time-course of cortical reorganization by measuring for the first time EEG cortical activity evoked by TMS pulses in patients with subcortical stroke. Thirteen patients in the sub-acute phase of ischemic subcortical stroke with motor symptoms completed the longitudinal study, being evaluated within 20 days and after 40, 60 and 180 days after stroke onset. For each time-point, EEG cortical activity evoked by single TMS pulses was assessed over the motor and parietal cortex of the affected and unaffected hemisphere. We evaluated global TMS-evoked activity and TMS-evoked oscillations in different frequency bands. These measurements were paralleled with clinical and behavioral assessment. We found that motor cortical activity measured by TMS-EEG varied across time in the affected hemisphere. An increase of TMS-evoked activity was evident at 40 days after stroke onset. Moreover, stroke patients showed a significant increase in TMS-evoked alpha oscillations, as highlighted performing analysis in the time-frequency domain. Notably, these changes indicated that crucial mechanisms of cortical reorganization occur in this short-time window. These changes coincided with the clinical improvement. TMS-evoked alpha oscillatory activity recorded at baseline was associated to better functional recovery at 40 and 60 days' follow-up evaluations, suggesting that the power of the alpha rhythm can be considered a good predictor of motor recovery. This study demonstrates that cortical activity increases dynamically in the early phases of recovery after stroke in the affected hemisphere. These findings point to TMS-evoked alpha oscillatory activity as a potential neurophysiological markers of stroke recovery and could be helpful to determine the temporal window in which neuromodulation should be potentially able to drive neuroplasticity in an effective functional direction.

Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease.

Memory loss is one of the first symptoms of typical Alzheimer's disease (AD), for which there are no effective therapies available. The precuneus (PC) has been recently emphasized as a key area for the memory impairment observed in early AD, likely due to disconnection mechanisms within large-scale networks such as the default mode network (DMN). Using a multimodal approach we investigated in a two-week, randomized, sham-controlled, double-blinded trial the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the PC on cognition, as measured by the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite in 14 patients with early AD (7 females). TMS combined with electroencephalography (TMS-EEG) was used to detect changes in brain connectivity. We found that rTMS of the PC induced a selective improvement in episodic memory, but not in other cognitive domains. Analysis of TMS-EEG signal revealed an increase of neural activity in patients' PC, an enhancement of brain oscillations in the beta band and a modification of functional connections between the PC and medial frontal areas within the DMN. Our findings show that high-frequency rTMS of the PC is a promising, non-invasive treatment for memory dysfunction in patients at early stages of AD. This clinical improvement is accompanied by modulation of brain connectivity, consistently with the pathophysiological model of brain disconnection in AD.

CSF tau is associated with impaired cortical plasticity, cognitive decline and astrocyte survival only in APOE4-positive Alzheimer's disease.

In Alzheimer's disease (AD) patients, apopoliprotein (APOE) polymorphism is the main genetic factor associated with more aggressive clinical course. However, the interaction between cerebrospinal fluid (CSF) tau protein levels and APOE genotype has been scarcely investigated. A possible key mechanism invokes the dysfunction of synaptic plasticity. We investigated how CSF tau interacts with APOE genotype in AD patients. We firstly explored whether CSF tau levels and APOE genotype influence disease progression and long-term potentiation (LTP)-like cortical plasticity as measured by transcranial magnetic stimulation (TMS) in AD patients. Then, we incubated normal human astrocytes (NHAs) with CSF collected from sub-groups of AD patients to determine whether APOE genotype and CSF biomarkers influence astrocytes survival. LTP-like cortical plasticity differed between AD patients with apolipoprotein E4 (APOE4) and apolipoprotein E3 (APOE3) genotype. Higher CSF tau levels were associated with more impaired LTP-like cortical plasticity and faster disease progression in AD patients with APOE4 but not APOE3 genotype. Apoptotic activity was higher when cells were incubated with CSF from AD patients with APOE4 and high tau levels. CSF tau is detrimental on cortical plasticity, disease progression and astrocyte survival only when associated with APOE4 genotype. This is relevant for new therapeutic approaches targeting tau.

Left hemispheric breakdown of LTP-like cortico-cortical plasticity in schizophrenic patients.

OBJECTIVE: Altered cortical connectivity and plasticity seems to be asymmetrical between the hemispheres in patients with schizophrenia (SCZ). We evaluated long-term potentiation (LTP) in parietal-frontal circuits of both hemispheres using a cortico-cortical Paired Associative Stimulation (cc-PAS) protocol testing the rules of Hebbian-like spike timing dependent plasticity (SPTD). METHODS: 12 SCZ and 12 healthy subjects (HS) underwent a cc-PAS protocol to activate, by means of paired pulses of transcranial magnetic stimulation (TMS), the short-latency connection between posterior parietal cortex (PPC) and primary motor cortex (M1) of both hemispheres. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity. RESULTS: While HS showed a similar time course of LTP-like plasticity in the two hemispheres, SCZ revealed a weaker late-LTP-like plasticity in the left compared to the right hemisphere after cc-PAS protocol. CONCLUSIONS: SCZ failed to show the typical long-lasting increase of M1 excitability observed after cc-PAS protocol in both hemispheres, with a greater reduction in the left one. SIGNIFICANCE: Our findings provide novel neurophysiological evidence for an asymmetric impairment of the left parietal-frontal network in SCZ patients.