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Pascual-Leone, Alvaro

Sustaining brain and cognitive function across the lifespan must be one of the main biomedical goals of the twenty-first century. We need to aim to prevent neuropsychiatric diseases and, thus, to identify and remediate brain and cognitive dysfunction before clinical symptoms manifest and disability develops. The brain undergoes a complex array of changes from developmental years into old age, putatively the underpinnings of changes in cognition and behavior throughout life. A functionally “normal” brain is a changing brain, a brain whose capacity and mechanisms of change are shifting appropriately from one time-point to another in a given individual's life. Therefore, assessing the mechanisms of brain plasticity across the lifespan is critical to gain insight into an individual's brain health. Indexing brain plasticity in humans is possible with transcranial magnetic stimulation (TMS), which, in combination with neuroimaging, provides a powerful tool for exploring local cortical and brain network plasticity. Here, we review investigations to date, summarize findings, and discuss some of the challenges that need to be solved to enhance the use of TMS measures of brain plasticity across all ages. Ultimately, TMS measures of plasticity can become the foundation for a brain health index (BHI) to enable objective correlates of an individual's brain health over time, assessment across diseases and disorders, and reliable evaluation of indicators of efficacy of future preventive and therapeutic interventions.

Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.

Deceptive abilities have long been studied in relation to personality traits. More recently, studies explored the neural substrates associated with deceptive skills suggesting a critical role of the prefrontal cortex. Here we investigated whether non-invasive brain stimulation over the dorsolateral prefrontal cortex (DLPFC) could modulate generation of untruthful responses about subject’s personal life across contexts (i.e., deceiving on guilt-free questions on daily activities; generating previously memorized lies about past experience; and producing spontaneous lies about past experience), as well as across modality responses (verbal and motor responses). Results reveal that real, but not sham, transcranial direct current stimulation (tDCS) over the DLPFC can reduce response latency for untruthful over truthful answers across contexts and modality responses. Also, contexts of lies seem to incur a different hemispheric laterality. These findings add up to previous studies demonstrating that it is possible to modulate some processes involved in generation of untruthful answers by applying non-invasive brain stimulation over the DLPFC and extend these findings by showing a differential hemispheric contribution of DLPFCs according to contexts.

The developmental pathophysiology of autism spectrum disorders (ASD) is currently not fully understood. However, multiple lines of evidence suggest that the behavioral phenotype may result from dysfunctional inhibitory control over excitatory synaptic plasticity. Consistent with this claim, previous studies indicate that adults with Asperger’s Syndrome show an abnormally extended modulation of corticospinal excitability following a train of repetitive transcranial magnetic stimulation (rTMS). As ASD is a developmental disorder, the current study aimed to explore the effect of development on the duration of modulation of corticospinal excitability in children and adolescents with ASD. Additionally, as the application of rTMS to the understanding and treatment of pediatric neurological and psychiatric disorders is an emerging field, this study further sought to provide evidence for the safety and tolerability of rTMS in children and adolescents with ASD. Corticospinal excitability was measured by applying single pulses of TMS to the primary motor cortex both before and following a 40 s train of continuous theta burst stimulation. 19 high-functioning males ages 9–18 with ASD participated in this study. Results from this study reveal a positive linear relationship between age and duration of modulation of rTMS after-effects. Specifically we found that the older participants had a longer lasting response. Furthermore, though the specific protocol employed typically suppresses corticospinal excitability in adults, more than one third of our sample had a paradoxical facilitatory response to the stimulation. Results support the safety and tolerability of rTMS in pediatric clinical populations. Data also support published theories implicating aberrant plasticity and GABAergic dysfunction in this population.

Human sensory and motor systems provide the natural means for the exchange of information between individuals, and, hence, the basis for human civilization. The recent development of brain-computer interfaces (BCI) has provided an important element for the creation of brain-to-brain communication systems, and precise brain stimulation techniques are now available for the realization of non-invasive computer-brain interfaces (CBI). These technologies, BCI and CBI, can be combined to realize the vision of non-invasive, computer-mediated brain-to-brain (B2B) communication between subjects (hyperinteraction). Here we demonstrate the conscious transmission of information between human brains through the intact scalp and without intervention of motor or peripheral sensory systems. Pseudo-random binary streams encoding words were transmitted between the minds of emitter and receiver subjects separated by great distances, representing the realization of the first human brain-to-brain interface. In a series of experiments, we established internet-mediated B2B communication by combining a BCI based on voluntary motor imagery-controlled electroencephalographic (EEG) changes with a CBI inducing the conscious perception of phosphenes (light flashes) through neuronavigated, robotized transcranial magnetic stimulation (TMS), with special care taken to block sensory (tactile, visual or auditory) cues. Our results provide a critical proof-of-principle demonstration for the development of conscious B2B communication technologies. More fully developed, related implementations will open new research venues in cognitive, social and clinical neuroscience and the scientific study of consciousness. We envision that hyperinteraction technologies will eventually have a profound impact on the social structure of our civilization and raise important ethical issues.

Background: There is increasing interest in the use of non-invasive brain stimulation to characterize and potentially treat essential tremor (ET). Studies have used a variety of stimulation coils, paradigms, and target locations to make these observations. We reviewed the literature to compare prior studies and to evaluate the rationale and the methods used in these studies. Methods: We performed a systematic literature search of the PubMed database using the terms “transcranial,” “noninvasive,” “brain stimulation,” “transcranial magnetic stimulation (TMS),” “transcranial direct current stimulation (tDCS),” “transcranial alternating current stimulation (tACS),” and “essential tremor.” Results: Single pulses of TMS to the primary motor cortex have long been known to reset tremor. Although there are relatively few studies showing alterations in motor cortical physiology, such as motor threshold, short and long intracortical inhibition, and cortical silent period, there may be some evidence of altered intracortical facilitation and cerebello-brain inhibition in ET. Repetitive TMS, theta burst stimulation, tDCS, and tACS have been applied to human subjects with tremor with some preliminary signs of tremor reduction, particularly in those studies that employed consecutive daily sessions. Discussion A variety of stimulation paradigms and targets have been explored, with the increasing rationale an interest in targeting the cerebellum. Rigorous assessment of coil geometry, stimulation paradigm, rationale for selection of the specific anatomic target, and careful phenotypic and physiologic characterization of the subjects with ET undergoing these interventions may be critical in extending these preliminary findings into effective stimulation therapies.

Acetylcholinesterase inhibitors (AChEIs) are the most commonly prescribed monotherapeutic medications for Alzheimer’s disease (AD). However, their underlying neurophysiological effects remain largely unknown. We investigated the effects of monotherapy (AChEI) and combination therapy (AChEI and memantine) on brain reactivity and plasticity. Patients treated with monotherapy (AChEI) (N = 7) were compared to patients receiving combination therapy (COM) (N = 9) and a group of age-matched, healthy controls (HCs) (N = 13). Cortical reactivity and plasticity of the motor cortex were examined using transcranial magnetic stimulation. Cognitive functions were assessed with the cognitive subscale of the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), activities of daily living (ADLs) with the ADCS-ADL. In addition we assessed the degree of brain atrophy by measuring brain-scalp distances in seven different brain areas. Patient groups differed in resting motor threshold and brain atrophy, with COM showing a lower motor threshold but less atrophy than AChEI. COM showed similar plasticity effects as the HC group, while plasticity was reduced in AChEI. Long-interval intracortical inhibition (LICI) was impaired in both patient groups when compared to HC. ADAS-Cog scores were positively correlated with LICI measures and with brain atrophy, specifically in the left inferior parietal cortex. AD patients treated with mono- or combination-therapy show distinct neurophysiological patterns. Further studies should investigate whether these measures might serve as biomarkers of treatment response and whether they could guide other therapeutic interventions.

It is well established that the human brain reorganizes following sensory deprivations. In blind individuals, visual processing regions including the lateral occipital cortex (LOC) are activated by auditory and tactile stimuli as demonstrated by neurophysiological and neuroimaging investigations. The mechanisms for such plasticity remain unclear, but shifts in connectivity across existing neural networks appear to play a critical role. The majority of research efforts to date have focused on neuroplastic changes within visual unimodal regions, however we hypothesized that neuroplastic alterations may also occur in brain networks beyond the visual cortices including involvement of multimodal integration regions and heteromodal cortices. In this study, two recently developed graph-theory based functional connectivity analyses, interconnector analyses and local and distant connectivity, were applied to investigate functional reorganization in regional and distributed neural-systems in late-onset blind (LB) and congenitally blind (CB) cohorts each compared to their own group of sighted controls. While functional network alterations as measured by the degree of differential links (DDL) occurred in sensory cortices, neuroplastic changes were most prominent within multimodal and association cortices. Subjects with LB showed enhanced multimodal integration connections in the parieto-opercular, temporoparietal junction (TPJ) and ventral premotor (vPM) regions, while CB individuals exhibited increased superior parietal cortex (SPC) connections. This study reveals the critical role of recipient multi-sensory integration areas in network reorganization and cross-modal plasticity in blind individuals. These findings suggest that aspects of cross-modal neuroplasticity and adaptive sensory-motor and auditory functions may potentially occur through reorganization in multimodal integration regions.

Background: Electroencephalographic (EEG) microstate analysis is a method of identifying quasi-stable functional brain states (“microstates”) that are altered in a number of neuropsychiatric disorders, suggesting their potential use as biomarkers of neurophysiological health and disease. However, use of EEG microstates as neurophysiological biomarkers requires assessment of the test-retest reliability of microstate analysis. Methods: We analyzed resting-state, eyes-closed, 30-channel EEG from 10 healthy subjects over 3 sessions spaced approximately 48 hours apart. We identified four microstate classes and calculated the average duration, frequency, and coverage fraction of these microstates. Using Cronbach's α and the standard error of measurement (SEM) as indicators of reliability, we examined: (1) the test-retest reliability of microstate features using a variety of different approaches; (2) the consistency between TAAHC and k-means clustering algorithms; and (3) whether microstate analysis can be reliably conducted with 19 and 8 electrodes. Results: The approach of identifying a single set of “global” microstate maps showed the highest reliability (mean Cronbach's α>0.8, SEM ≈10% of mean values) compared to microstates derived by each session or each recording. There was notably low reliability in features calculated from maps extracted individually for each recording, suggesting that the analysis is most reliable when maps are held constant. Features were highly consistent across clustering methods (Cronbach's α>0.9). All features had high test-retest reliability with 19 and 8 electrodes. Conclusions: High test-retest reliability and cross-method consistency of microstate features suggests their potential as biomarkers for assessment of the brain's neurophysiological health.