Cortico-cortical connectivity: the road from basic neurophysiological interactions to therapeutic applications.

Transcranial magnetic stimulation (TMS) based methods are emerging as a unique approach to evaluate in real-time brain electrical activity in healthy and pathological conditions. By applying TMS pulses in two different bran areas within a short temporal frame of few milliseconds, it is possible to investigate their physiological interactions. These paradigms, collectively termed dual-site TMS, have been inspired by Professor John Rothwell's work, based on the idea that applying a conditioning stimulus over a cortical area may activate putative pathways projecting onto a second target area, thus providing a unique opportunity to test the causal effects between interconnected brain areas.

Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.

Background: Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations.

Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability.

Mutations in REEP1 have been identified in three types of neurological disorders, autosomal dominant form of Hereditary Spastic Paraplegia type 31 (SPG31), autosomal dominant distal hereditary motor neuronopathy type VB (HMN5B), and autosomal recessive form of congenital axonal neuropathy and diaphragmatic palsy. Previous studies demonstrated different molecular pathogenesis in SPG31, including loss-of-function, gain-of-function and haploinsufficiency. A four-generation family from Japan, including 12 members, was investigated clinically and genetically.

Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability.

Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation. This study is to explore the novel SPAST splice site donor variant, c.

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.

A role for NMDAR-dependent cerebellar plasticity in adaptive control of saccades in humans.

Background: Saccade pulse amplitude adaptation is mediated by the dorsal cerebellar vermis and fastigial nucleus. Long-term depression at the parallel fibre-Purkinjie cell synapses has been suggested to provide a cellular mechanism for the corresponding learning process. The mechanisms and sites of this plasticity, however, are still debated.

Trans-crocetin improves amyloid-β degradation in monocytes from Alzheimer's Disease patients.

Herbal medicines have been recently employed in research and clinical studies for the potential treatment of behavioral and psychological symptoms associated with Alzheimer's Disease (AD) and other types of dementia. The present study investigates the effect of trans-crocetin, an active constituent of Crocus sativus L., to restore in vitro the reduced ability of AD patients' monocytes to degrade amyloid-β (Aβ).

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.

Neuronal mechanisms of motor learning are age dependent.

There is controversy whether age-related neuroanatomical and neurophysiological changes in the central nervous system affect healthy old adults' abilities to acquire and retain motor skills. We examined the effects of age on motor skill acquisition and retention and potential underlying mechanisms by measuring corticospinal and intracortical excitability, using transcranial magnetic stimulation. Healthy young (n = 24, 22 years) and old (n = 22, 71 years) adults practiced a wrist flexion-extention visuomotor task or only watched the templates as an attentional control for 20 minutes.

ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis.

Abnormal asymmetry of brain connectivity in schizophrenia.

Recently, a growing body of data has revealed that beyond a dysfunction of connectivity among different brain areas in schizophrenia patients (SCZ), there is also an abnormal asymmetry of functional connectivity compared with healthy subjects. The loss of the cerebral torque and the abnormalities of gyrification, with an increased or more complex cortical folding in the right hemisphere may provide an anatomical basis for such aberrant connectivity in SCZ. Furthermore, diffusion tensor imaging studies have shown a significant reduction of leftward asymmetry in some key white-matter tracts in SCZ.

Parieto-motor cortical dysfunction in primary cervical dystonia.

Background: Dystonia is considered as a motor network disorder involving the dysfunction of the posterior parietal cortex, a region involved in preparing and executing reaching movements.

Objective/hypothesis: We used transcranial magnetic stimulation to test the hypothesis that cervical dystonic patients may have a disrupted parieto-motor connectivity.

Methods: We enrolled 14 patients with primary cervical dystonia and 14 controls.

Exploring the reciprocal modulation of time and space in dancers and non-dancers.

We explored whether time and space representations modulate each other in subjects that are trained to integrate time and space dimensions, i.e., professional dancers.

Maladaptive plasticity in levodopa-induced dyskinesias and tardive dyskinesias: old and new insights on the effects of dopamine receptor pharmacology.

Maladaptive plasticity can be defined as behavioral loss or even development of disease symptoms resulting from aberrant plasticity changes in the human brain. Hyperkinetic movement disorders, in the neurological or psychiatric realms, have been associated with maladaptive neural plasticity that can be expressed by functional changes such as an increase in transmitter release, receptor regulation, and synaptic plasticity or anatomical modifications such as axonal regeneration, sprouting, synaptogenesis, and neurogenesis. Recent evidence from human and animal models provided support to the hypothesis that these phenomena likely depend on altered dopamine turnover induced by long-term drug treatment.

Theta burst stimulation improves visuo-spatial attention in a patient with traumatic brain injury.

Recent studies showed that non-invasive brain stimulation methods, such as repetitive transcranial magnetic stimulation (rTMS) can improve the symptoms of neglect in stroke patients. Here, we adopted this approach to improve visuo-spatial deficit in a patient with traumatic brain injury (TBI) that showed important symptoms of visuo-spatial neglect. We found that continuous theta burst stimulation (cTBS) applied over the left posterior parietal cortex (PPC) induced a clinical improvement of cognitive disorder associated to a functional changes of fronto-parietal network as assessed by means of TMS and resting state fMRI.

Keeping memory for intentions: a cTBS investigation of the frontopolar cortex.

The present study aimed to investigate the role of frontopolar cortex in prospective memory (PM) by means of inhibitory theta-burst stimulation (cTBS). "Experiment 1"-8 volunteers were evaluated after inhibitory cTBS over left Brodmann area (BA) 10, right BA10, and Cz. In the PM procedure, sequences of 4 words each were presented.

rTMS effects on levodopa induced dyskinesias in Parkinson's disease patients: searching for effective cortical targets.

Long-term therapy with levodopa and dopamine agonists in Parkinson's disease (PD) patients is complicated by the development of fluctuations in motor response, such as levo-dopa induced dyskinesia (LID). Repetitive Transcranial Magnetic Stimulation (rTMS) has been recently put forward as a possible therapeutic tool able to LID in PD. Trains of 1 Hz rTMS applied either over the supplementary motor area (SMA) or the primary motor cortex (M1) were able to induce a transient reduction in the severity of LID, confirming that an over-activity of these areas plays a crucial role in the pathophysiology of LID.

TMS activation of interhemispheric pathways between the posterior parietal cortex and the contralateral motor cortex.

Using a twin coil transcranial magnetic stimulation (tc-TMS) approach we have previously demonstrated that facilitation may be detected in the primary motor cortex (M1) following stimulation over the ipsilateral caudal intraparietal sulcus (cIPS). Here we tested the interhemispheric interactions between the IPS and the contralateral motor cortex (M1). We found that conditioning the right cIPS facilitated contralateral M1 when the conditioning stimulus had an intensity of 90% resting motor threshold (RMT) but not at 70% or 110% RMT.

Cerebellar magnetic stimulation decreases levodopa-induced dyskinesias in Parkinson disease.

Background: The neural mechanisms and the circuitry involved in levodopa-induced dyskinesia (LID) are still partially obscure. LID can be considered the consequence of an abnormal pattern or code of activity that originates and is conveyed from the basal ganglia to the thalamus and the cortical motor areas. However, not only striatothalamocortical motor circuits but also other interconnected pathways could be implicated in its pathogenesis.

Effects of deep brain stimulation of the peduncolopontine area on working memory tasks in patients with Parkinson's disease.

The present paper was aimed at investigating the effect of low-frequency electrical stimulation (25 Hz) of the peduncolopontine (PPN) area on working memory (WM) functioning in patients with Parkinson's disease (PD). Five PD patients who underwent simultaneous PPN area- and subthalamic nucleus-deep brain stimulation (DBS) implantation participated in the study. PD patients were evaluated in the morning at least 12 h after antiparkinsonian therapy withdrawal in two conditions: i) after continuous PPN area stimulation (Off Therapy/On PPN: "On" condition); ii) at least 120 min after PPN area had been switched "Off" (Off Ther/Off PPN: "Off" condition).

Neural networks engaged in milliseconds and seconds time processing: evidence from transcranial magnetic stimulation and patients with cortical or subcortical dysfunction.

Here, we review recent transcranial magnetic stimulation studies and investigations in patients with neurological disease such as Parkinson's disease and stroke, showing that the neural processing of time requires the activity of wide range-distributed brain networks. The neural activity of the cerebellum seems most crucial when subjects are required to quickly estimate the passage of brief intervals, and when time is computed in relation to precise salient events. Conversely, the circuits involving the striatum and the substantia nigra projecting to the prefrontal cortex (PFC) are mostly implicated in supra-second time intervals and when time is processed in conjunction with other cognitive functions.

TMS investigations into the task-dependent functional interplay between human posterior parietal and motor cortex.

Transcranial magnetic stimulation (TMS) can be used in two different ways to investigate the contribution of cortical areas involved in grasp/reach movements in humans. It can produce "virtual lesions" that interfere with activity in particular cortical areas at specific times during a task, or it can be used in a twin coil design to test the excitability of cortical projections to M1 at different times during a task. The former method has described how cortical structures such as the ventral premotor cortex (PMv), dorsal premotor cortex (PMd) and the anterior intraparietal sulcus (aIPS) are important for specific aspects of reaching, grasping and lifting objects.