Synaptic Plasticity by Afferent Electrical Stimulation

The effect of afferent electrical stimulation on synaptic plasticity within the sensorimotor cortex will be discussed. Afferent electrical stimulation induces a down regulation of inhibitory neural circuits and plays a critical role in strengthening excitatory synapses. Synaptic modifications such as long-term potentiation (LTP) mechanisms could be a crucial mechanism underlying this stimulation-induced cortical plasticity. LTP and long-term depression (LTD) of synaptic transmission are crucial factors for activity-dependent changes in the strength of synaptic connections. Many studies demonstrated that these pathways play an important role in cortical synaptic plasticity. Repeated activation of excitatory synapses induces both short-term potentiation (STP) and LTP. Both types of synaptic potentiation affect N-methyl-D-aspartate glutamate receptors leading to the formation of new synapses or the unmasking of excitatory amino acid receptors on motor neurons. This increased excitability localized within the sensorimotor cortex may reflect an increase in neuronal activity as a result of a dynamic interaction of various synaptic and cellular mechanisms due to the local processing of afferent electrical input to the sensorimotor cortex. The chapter reviews also the large number of studies using fMRI and TMS to examine the effects of afferent electrical input from the hand on the excitability of human sensorimotor cortex

Electrophysiological Assessment of CNS Abnormalities in Muscular Dystrophy

Patients affected by muscular dystrophies often show CNS abnormalities. Patients with dystrophinopathies exhibit intellectual disabilities and mental retardation, while subjects with facioscapulohumeral muscular dystrophy (FSHD) often show epilepsy. Dystrophin and associated proteins have important roles in the CNS. Many patients with Duchenne and Becker muscular dystrophies (DMD/BMD) have cognitive impairment, learning disability, and variable degrees of mental retardation in addition to progressive muscular weakness. Unfortunately, the assessment of cortical function with TMS in DMD patients has not been able to delineate a clear picture and has yielded contradictory results. No TMS studies have been performed on BMD patients. Repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability, possibly by inducing a short-term increase in synaptic efficacy, and can be used to investigate motor cortex excitability in BMD patients. Changes in the size and threshold of motor evoked potentials (MEPs) and cortical silent period (CSP) duration evoked by rTMS delivered in 5 Hz trains of stimuli at suprathreshold intensity can be tested. Impaired muscular function might be partially compensated by an enhancement of motor excitability at the cortical level and/or at α-motoneuron level. TMS may thus offer a reliable means to characterize also important neurophysiologic and pathophysiologic aspects of cortical involvement in muscular dystrophy

Transcranial Magnetic Stimulation and Cognitive Impairment

With transcranial magnetic stimulation (TMS), the motor system in neuropsychiatric disorders has extensively been investigated, and effects of certain pharmacological agents have been monitored. The most consistent finding in neuropsychiatric disorders is a significant reduction of short-latency afferent inhibition (SAI). SAI provides a reliable biomarker of cortical cholinergic dysfunction in neuropsychiatric disorders. Cortical hyperexcitability and asymptomatic motor cortex functional reorganization in the early stages of neuropsychiatric disorders have been demonstrated by TMS. Together with high-density EEG TMS and paired-associative stimulation, TMS showed impaired cortical plasticity and functional connectivity across different neural networks in neuropsychiatric disorders. Neuromodulatory techniques, especially as repetitive TMS (rTMS), hold promise as a therapeutic tool for cognitive rehabilitation because rTMS can enhance cognitive functions in neuropsychiatric disorders

Deactivation of the Default Mode Network as a Marker of Impaired Consciousness: An fMRI Study

Diagnosis of patients with a disorder of consciousness is very challenging. Previous studies investigating resting state networks demonstrate that 2 main features of the so-called default mode network (DMN), metabolism and functional connectivity, are impaired in patients with a disorder of consciousness. However, task-induced deactivation – a third main feature of the DMN – has not been explored in a group of patients. Deactivation of the DMN is supposed to reflect interruptions of introspective processes. Seventeen patients with unresponsive wakefulness syndrome (UWS, former vegetative state), 8 patients in minimally conscious state (MCS), and 25 healthy controls were investigated with functional magnetic resonance imaging during a passive sentence listening task. Results show that deactivation in medial regions is reduced in MCS and absent in UWS patients compared to healthy controls. Moreover, behavioral scores assessing the level of consciousness correlate with deactivation in patients. On single-subject level, all control subjects but only 2 patients in MCS and 6 with UWS exposed deactivation. Interestingly, all patients who deactivated during speech processing (except for one) showed activation in left frontal regions which are associated with conscious processing. Our results indicate that deactivation of the DMN can be associated with the level of consciousness by selecting those who are able to interrupt ongoing introspective processes. In consequence, deactivation of the DMN may function as a marker of consciousness

Effect of Transcranial Brain Stimulation for the Treatment of Alzheimer Disease: A Review

Available pharmacological treatments for Alzheimer disease (AD) have limited effectiveness, are expensive, and sometimes induce side effects. Therefore, alternative or complementary adjuvant therapeutic strategies have gained increasing attention. The development of novel noninvasive methods of brain stimulation has increased the interest in neuromodulatory techniques as potential therapeutic tool for cognitive rehabilitation in AD. In particular, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive approaches that induce prolonged functional changes in the cerebral cortex. Several studies have begun to therapeutically use rTMS or tDCS to improve cognitive performances in patients with AD. However, most of them induced short-duration beneficial effects and were not adequately powered to establish evidence for therapeutic efficacy. Therefore, TMS and tDCS approaches, seeking to enhance cognitive function, have to be considered still very preliminary. In future studies, multiple rTMS or tDCS sessions might also interact, and metaplasticity effects could affect the outcome

Effects of rubber hand illusion and excitatory theta burst stimulation on tactile sensation: A pilot study

Synchronous visuotactile stimulation on the own hidden hand and a visible fake limb can alter bodily self-perception and influence spontaneous neuroplasticity. The rubber hand illusion (RHI) paradigm experimentally produces an illusion of rubber hand ownership and arm shift by simultaneously stroking a rubber hand in view and a participant's visually occluded hand. The aim of this cross-over, placebo-controlled, single-blind study was to assess whether RHI, in combination with high-frequency repetitive transcranial magnetic stimulation (rTMS) given as intermittent (excitatory) theta burst stimulation (iTBS) applied over the hand area of the primary sensory region (S1) can enhance tactile sensation in a group of 21 healthy subjects and one patient with cervical spinal cord injury. Four sessions covered all combinations of real and sham stimulations of the RHI and the TBS: Real TBS and real RHI, real TBS and sham RHI, sham TBS and real RHI, and both conditions sham. The condition sham TBS and real RHI shows the greatest effect on the proprioceptive drift (median 2.3 cm, IQR 2) and on the score of RHI questionnaires (median 3, IQR 2) in the control group as well as in the real-real condition (median 2, IQR 2). The sham TBS and real RHI condition also shows the best results in the electrical perception test of the patient (median 1.9 mA). Conversely, the upregulation of the cortical excitability of S1 via TBS seems to impair the effect of the RHI. This might be due to a strengthening of the top-down connection between the central nervous system and the periphery, diminishing the RHI. This finding helps in understanding the mechanisms of top-down and bottom-up mechanisms in healthy subjects and patients with spinal cord injury. The RHI paradigm could represent an interesting therapeutic approach in improving tactile sensation and rTMS techniques could modulate these effects. Yet, further studies are needed, to examine the direction of the interaction effect of TMS and RH.Spinal Cord Injury and Tissue Regeneration Center SalzburgPeer Reviewe

Usefulness of EEG Techniques in Distinguishing Frontotemporal Dementia from Alzheimer's Disease and Other Dementias

The clinical distinction of frontotemporal dementia (FTD) and Alzheimer's disease (AD) may be difficult. In this narrative review we summarize and discuss the most relevant electroencephalography (EEG) studies which have been applied to demented patients with the aim of distinguishing the various types of cognitive impairment. EEG studies revealed that patients at an early stage of FTD or AD displayed different patterns in the cortical localization of oscillatory activity across different frequency bands and in functional connectivity. Both classical EEG spectral analysis and EEG topography analysis are able to differentiate the different dementias at group level. The combination of standardized low-resolution brain electromagnetic tomography (sLORETA) and power parameters seems to improve the sensitivity, but spectral and connectivity biomarkers able to differentiate single patients have not yet been identified. The promising EEG findings should be replicated in larger studies, but could represent an additional useful, noninvasive, and reproducible diagnostic tool for clinical practice

Lymphocyte Subsets Show Different Response Patterns to In Vivo Bound Natalizumab—A Flow Cytometric Study on Patients with Multiple Sclerosis

Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing- remitting multiple sclerosis (RRMS) and interferes with immune cell migration into the central nervous system by blocking the α4 subunit of very-late activation antigen-4 (VLA-4). Although well tolerated and very effective, some patients still suffer from relapses in spite of natalizumab therapy or from unwanted side effects like progressive multifocal leukoencephalopathy (PML). In search of a routine-qualified biomarker on the effectiveness of natalizumab therapy we applied flow cytometry and analyzed natalizumab binding to α4 and α4 integrin surface levels on T-cells, B-cells, natural killer (NK) cells, and NKT cells from 26 RRMS patients under up to 72 weeks of therapy. Four-weekly infusions of natalizumab resulted in a significant and sustained increase of lymphocyte-bound natalizumab (p<0.001) which was paralleled by a significant decrease in detectability of the α4 integrin subunit on all lymphocyte subsets (p<0.001). We observed pronounced natalizumab accumulations on T and B cells at single measurements in all patients who reported clinical disease activity (n = 4). The natalizumab binding capacity of in vitro saturated lymphocytes collected during therapy was strongly diminished compared to treatment-naive cells indicating a therapy-induced reduction of α4. Summing up, this pilot study shows that flow cytometry is a useful method to monitor natalizumab binding to lymphocytes from RRMS patients under therapy. Investigating natalizumab binding provides an opportunity to evaluate the molecular level of effectiveness of natalizumab therapy in individual patients. In combination with natalizumab saturation experiments, it possibly even provides a means of studying the feasability of patient-tailored infusion intervals. A routine-qualified biomarker on the basis of individual natalizumab saturation on lymphocyte subsets might be an effective tool to improve treatment safety

Functional Magnetic Resonance Imaging in the Final Stage of Creutzfeldt-Jakob Disease

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare fatal degenerative disease of the central nervous system. The clinical course is characterized by rapid progression of neurological and neuromuscular symptoms. The late stage with loss of consciousness is not well characterized. We report a 62-year-old male patient with sCJD with the clinical picture of a vegetative state/apallic syndrome, in whom we studied cortical responses using a vibration paradigm. The functional magnetic resonance imaging (fMRI) investigation demonstrated a clear response within the sensorimotor cortex, the cerebellum, the parietal cortex, the insular, and frontal inferior region. The finding of persistent cortical activity on fMRI in a patient with CJD in a state of unconsciousness has implications for the clinical management and for ethical considerations