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.

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.

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.

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.

Real-time activation of central cholinergic circuits during recognition memory.

Short latency afferent inhibition (SAI) is a paired-pulse transcranial magnetic stimulation (TMS) protocol that consists in the inhibition of the motor evoked potentials (MEPs) by afferent sensory impulses. SAI is thought to be mediated by cholinergic projections over M1 and can be considered a putative marker of central cholinergic activity. It is known that memory processes are regulated by acetylcholine. Nonetheless, the influence of memory tasks on SAI has not been investigated. Here we tested changes in SAI circuits in healthy subjects performing a computerized non-verbal recognition memory task (RMT) requiring to recognize previously encoded faces. SAI protocol was recorded during five phases of the RMT: baseline, encoding, consolidation, retrieval, and post-task. In the control task, subjects were asked to judge a visual feature of not previously presented faces. SAI protocol was applied over the same conditions as in the RMT. We found that SAI remarkably increases during the retrieval phase of the RMT as compared to baseline. On the other hand no change was observed during the control task. These findings show that SAI can be modulated by ongoing memory processes and support the hypothesis that SAI can be considered as a neurophysiological marker of central cholinergic activity.

Long-term potentiation-like cortical plasticity is disrupted in Alzheimer's disease patients independently from age of onset.

OBJECTIVE: Alzheimer's disease (AD) is considered an age-related disorder. However, it is unclear whether AD induces the same pathological and neurophysiological modifications in synaptic functions independently from age of disease onset. We used transcranial magnetic stimulation tools to investigate the mechanisms of cortical plasticity and sensory-motor integration in AD patients with a wide range of disease onset. METHODS: We evaluated newly diagnosed sporadic AD (n = 54) in comparison with healthy age-matched controls (HS; n = 24). Cortical plasticity mechanisms of long-term potentiation (LTP) or of long-term depression (LTD) were assessed using respectively intermittent (iTBS) or continuous theta burst stimulation (cTBS) protocols. Sensory-motor integration was evaluated by means of short afferent inhibition (SAI) protocol. RESULTS: AD patients show after iTBS an impairment of LTP-like cortical plasticity forming a paradoxical LTD in comparison to HS. LTD-like cortical plasticity is similar between AD and HS. LTP-like cortical plasticity is not associated with age, but AD patients presenting with more altered LTP-like cortical plasticity have more-severe cognitive decline at 18 months. SAI is impaired in AD and shows a strong association with the individual age of subjects rather than with disease age of onset. INTERPRETATION: Cortical LTP disruption is a central mechanism of AD that is independent from age of onset. AD can be described primarily as a disorder of LTP-like cortical plasticity not influenced by physiological aging and associated with a more-severe cognitive decline. Ann Neurol 2016;80:202-210.

Impaired intracortical transmission in G2019S leucine rich-repeat kinase Parkinson patients.

OBJECTIVES: A mutation in leucine-rich repeat kinase 2 is the most common cause of hereditary Parkinson's disease (PD), yet the neural mechanisms and the circuitry potentially involved are poorly understood. METHODS: We used different transcranial magnetic stimulation protocols to explore in the primary motor cortex the activity of intracortical circuits and cortical plasticity (long-term potentiation) in patients with the G2019S leucine-rich repeat kinase 2 gene mutation when compared with idiopathic PD patients and age-matched healthy subjects. Paired pulse transcranial magnetic stimulation was used to investigate short intracortical inhibition and facilitation and short afferent inhibition. Intermittent theta burst stimulation, a form of repetitive transcranial magnetic stimulation, was used to test long-term potentiation-like cortical plasticity. Leucine-rich repeat kinase 2 and idiopathic PD were tested both in ON and in OFF l-dopa therapy. RESULTS: When compared with idiopathic PD and healthy subjects, leucine-rich repeat kinase 2 PD patients showed a remarkable reduction of short intracortical inhibition in both ON and in OFF l-dopa therapy. This reduction was paralleled by an increase of intracortical facilitation in OFF l-dopa therapy. Leucine-rich repeat kinase 2 PD showed abnormal long-term potentiation-like cortical plasticity in ON l-dopa therapy. DISCUSSION: The motor cortex in leucine-rich repeat kinase 2 mutated PD patients is strongly disinhibited and hyperexcitable. These abnormalities could be a result of an impairment of inhibitory (gamma-Aminobutyric acid) transmission eventually related to altered neurotransmitter release. © 2017 International Parkinson and Movement Disorder Society.

Theta Burst Stimulation of the Precuneus Modulates Resting State Connectivity in the Left Temporal Pole.

It has been shown that continuous theta burst stimulation (cTBS) over the precuneus acts on specific memory retrieval abilities. In order to study the neural mechanisms beyond these findings, we combined cTBS and resting-state functional magnetic resonance imaging. Our experimental protocol involved stimulation and sham conditions on a group of healthy subjects, and each condition included a baseline and two follow-up acquisitions (5 and 15 min after baseline) after cTBS. We analysed brain functional connectivity by means of graph theoretical measures, with a specific focus on the network modular structure. Our results showed that cTBS of the precuneus selectively affects the left temporal pole, decreasing its functional connectivity in the first follow-up. Moreover, we observed a significant increase in the size of the module of the precuneus in the second follow-up. Such effects were absent in the sham condition. We observed here a modulation of functional connectivity as a result of inhibitory stimulation over the precuneus. Such a modulation first acts indirectly on the temporal area and then extends the connectivity of the precuneus itself by a feed-back mechanism. Our current findings extend our previous behavioural observations and increase our understanding of the mechanisms underlying the stimulation of the precuneus.

Altered inhibitory interaction among inferior frontal and motor cortex in l-dopa-induced dyskinesias.

BACKGROUND: Levodopa-induced dyskinesias are associated with thalamo-cortical disinhibition and frontal area overactivation. Neuroimaging and transcranial magnetic stimulation studies have highlighted the involvement of the right inferior frontal cortex in levodopa-induced dyskinesias. METHODS: Using transcranial magnetic stimulation, we tested connectivity between the inferior frontal and contralateral motor cortex in Parkinson's disease patients with and without levodopa-induced dyskinesias compared with age-matched controls. Furthermore, in dyskinetic patients, connectivity between the inferior frontal and contralateral motor cortex was assessed before and after a single session of continuous theta-burst stimulation applied over the inferior frontal cortex. RESULTS: Dyskinetic patients showed abnormal facilitatory connectivity between the inferior frontal and motor cortex when compared with the nondyskinetic group. Continuous theta-burst stimulation over the inferior frontal cortex eliminated such facilitatory connectivity and decreased the levodopa-induced dyskinesias that was induced by a supramaximal dose of levodopa. CONCLUSION: In dyskinetic patients, a weaker inhibitory cortico-cortical interaction between the inferior frontal and contralateral motor cortex could be involved in levodopa-induced dyskinesias and restored by continuous theta-burst stimulation over the inferior frontal cortex. © 2016 Movement Disorder Society.

Cerebellar Control on Prefrontal-Motor Connectivity During Movement Inhibition.

Converging evidence suggests a crucial role of right inferior frontal gyrus (r-IFG) and right pre-supplementary motor area (r-preSMA) in movement inhibition control. The present work was aimed to investigate how the effective connectivity between these prefrontal areas and the primary motor cortex could change depending on the activity of the cerebellar cortex. Paired transcranial magnetic stimulation (TMS) was delivered in healthy subjects over the r-IFG/left primary motor area (l-M1) and over r-preSMA/l-M1 before (100 ms after the fixation cross onset) and 50, 75, 100, 125, and 150 ms after the presentation of a Go/NoGo visual cue establishing the specific time course and the causal interactions of these regions in relation to l-M1 as measured by motor evoked potentials (MEPs). The same paired-pulse protocol was applied following sham or real cerebellar continuous theta burst stimulation (cTBS). Following sham cTBS, for NoGo trials only, MEPs collected showed the expected pattern of activation for both r-IFG-l-M1 and r-preSMA-l-M1 connectivity, characterized by peaks of increased and decreased MEP amplitude regularly repeated every 50 ms. Following cerebellar cTBS, this pattern of activation related to NoGo trials was modified selectively for the r-IFG-M1 but not for r-preSMA-M1 connection. A common monitoring action of r-IFG and r-preSMA in inhibitory control was confirmed. The effects of cerebellar cTBS showed a specific interaction between cerebellum and r-IFG activity during the inhibitory process.

Paradoxical facilitation after depotentiation protocol can precede dyskinesia onset in early Parkinson's disease.

Loss of dopamine, a key modulator of synaptic signalling, and subsequent pulsatile non-physiological levodopa replacement is believed to underlie altered neuroplasticity in Parkinson's disease (PD). Animal models suggest that maladaptive plasticity (e.g. deficient depotentiation at corticostriatal synapses) is key in the development of levodopa-induced dyskinesia (LID), a common complication following levodopa replacement in PD. Human studies using transcranial magnetic stimulation protocols have shown similar depotentiation deficit in patients with LID. We hypothesized that subtle depotentiation deficits should precede LID if these deficits are mechanistically linked to LID onset. Moreover, patients on pulsatile levodopa-based therapy may show these changes earlier than those treated with levodopa-sparing strategies. We recruited 22 early non-dyskinetic PD patients (<5 years since diagnosis) and 12 age-matched healthy controls. We grouped patients into those on Levodopa-Based (n = 11) and Levodopa-Sparing therapies (n = 11). Patients were selected to obtain groups matched for age and disease severity. We used a theta-burst stimulation protocol to investigate potentiation and depotentiation in a single session. We report significant depotentiation deficits in the Levodopa-Based group, compared to both Levodopa-Sparing and Healthy Control groups. Potentiation and Depotentiation responses were similar between Levodopa-Sparing and Healthy Control groups. Although differences persist after accounting for potential confounds (e.g. levodopa-equivalent dose), these results may yet be caused by differences in disease severity and cumulative levodopa-equivalent dose as discussed in the text. In conclusion, we show for the first time that paradoxical facilitation in response to depotentiation protocols can occur in PD even prior to LID onset.

A network centred on the inferior frontal cortex is critically involved in levodopa-induced dyskinesias.

Levodopa-induced dyskinesias are disabling motor complications of long-term dopamine replacement in patients with Parkinson's disease. In recent years, several alternative models have been proposed to explain the pathophysiological mechanisms underlying this hyperkinetic motor disorder. In particular, our group has shed new light on the role of the prefrontal cortex as a key site of interest, demonstrating that, among other areas, the inferior frontal cortex is particularly characterized by altered patterns of anatomical and functional changes. However, how neural activity varies depending on levodopa treatment in patients with dyskinesias and whether the reported prefrontal abnormalities may have a critical role in dyskinesias is debated. To answer these questions we performed independent functional magnetic resonance imaging and repetitive transcranial magnetic stimulation studies. In the first experiment we applied resting state functional magnetic resonance imaging on 12 patients with Parkinson's disease with levodopa-induced dyskinesias and 12 clinically matched patients without dyskinesias, before and after administration of levodopa. Functional connectivity of brain networks in the resting state was assessed in both groups. We chose the right inferior frontal cortex as the seed region given the evidence highlighting the role of this region in motor control. In a second experiment, we applied different forms of repetitive transcranial magnetic stimulation over the right inferior frontal cortex in a new group of dyskinetic patients who were taking a supramaximal dose of levodopa, to verify the clinical relevance of this area in controlling the development of hyperkinetic movements. The resting state functional imaging analysis revealed that in patients with levodopa-induced dyskinesias connectivity of the right inferior frontal cortex was decreased with the left motor cortex and increased with the right putamen when compared to patients without levodopa-induced dyskinesias. This abnormal pattern of connectivity was evident only during the ON phase of levodopa treatment and the degree of such alteration correlated with motor disability. The repetitive TMS experiments showed that a session of continuous but not intermittent or sham theta burst stimulation applied over the inferior frontal cortex was able to reduce the amount of dyskinesias induced by a supramaximal single dose of levodopa, suggesting that this area may play a key role in controlling the development of dyskinesias. Our combined resting state functional magnetic resonance and transcranial magnetic stimulation studies demonstrate that pathophysiological mechanisms underlying levodopa-induced dyskinesias may extend beyond the 'classical' basal ganglia dysfunctions model, including the modulation performed by the neural network centred on the inferior frontal cortex.

Paired associative stimulation enforces the communication between interconnected areas.

Paired associative stimulation (PAS) protocols induce forms of spike-timing-dependent-plasticity (STDP) when paired pulses are repeatedly applied with different timing over interconnected cortical areas such as the posterior parietal cortex (PPC) and the primary motor cortex (M1). However, the assessment of PAS effects is usually limited to M1 through recording of motor-evoked potential (MEP) amplitude. Here, by combining transcranial magnetic stimulation (TMS) with EEG we aimed at investigating PAS effects over both areas (PPC, M1) and the modulation induced on their connectivity in humans. In different PAS conditions, PPC preceded or followed M1 TMS by 5 ms. We found that TMS-evoked potentials (TEPs) changed differently according to the long-term depression (LTD) or potentiation (LTP) after-effect assessed by MEPs, but did not vary at PPC level. Moreover, there was no change in local oscillatory power. However, there was a remarkable increase of coherence between the PPC and the M1 areas. When the PAS protocol induced LTD as revealed by MEPs, there was a specific increase of the coherence between PPC and M1 within the beta band. On the contrary, when PAS induced LTP, the coherence crucially increased in the alpha band. The same LTP results were confirmed when rotating the stimulating coil in M1 during the PAS protocol. In conclusion, we report new evidence that opposite STDP-like effects induced by corticocortical PAS are associated with increased communication between involved brain areas and that antithetic forms of STDP-like after-effects result in distinct cortical rhythms connectivity changes.

Hebbian and anti-Hebbian spike-timing-dependent plasticity of human cortico-cortical connections.

Learning of new skills may occur through Hebbian associative changes in the synaptic strength of cortical connections [spike-timing-dependent plasticity (STDP)], but how the precise temporal relationship of the presynaptic and postsynaptic inputs determines the STDP effects in humans is poorly understood. We used a novel paired associative stimulation protocol to repeatedly activate the short-latency connection between the posterior parietal cortex and the primary motor cortex (M1) of the left-dominant hemisphere. In different experiments, we systematically varied the temporal relationships between the stimuli and the preferential activation of different M1 neuronal populations by applying transcranial magnetic stimulation over M1 with different coil orientations and in different states of cortical excitability (rest vs muscular contraction). We found evidence for the existence of both Hebbian and anti-Hebbian STDP in human long-range connections. The induction of bidirectional long-term potentiation or depression in M1 depended not only on the relative timing between the stimuli but, crucially, on the stimulation of specific neuronal populations and the activity state of the cortex. Our findings demonstrate that these mechanisms are not fixed but susceptible to rapid adaptations. This sudden transition from anti-Hebbian to Hebbian plasticity likely involves local dynamics of interaction with different populations of postsynaptic neurons.

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 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.

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.

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.