Gradual enhancement of corticomotor excitability during cortico-cortical paired associative stimulation

Cortico-cortical paired associative stimulation (ccPAS) is an effective transcranial magnetic stimulation (TMS) method for inducing associative plasticity between interconnected brain areas in humans. Prior ccPAS studies have focused on protocol’s aftereffects. Here, we investigated physiological changes induced “online” during ccPAS administration. We tested 109 participants receiving ccPAS over left ventral premotor cortex (PMv) and primary motor cortex (M1) using a standard procedure (90 paired-pulses with 8-ms interstimulus interval, repeated at 0.1 Hz frequency). On each paired-pulse, we recorded a motor-evoked potential (MEP) to continuously trace the emergence of corticomotor changes. Participant receiving forward-ccPAS (on each pair, a first TMS pulse was administered over PMv, second over M1, i.e., PMv-to-M1) showed a gradual and linear increase in MEP size that did not reach a plateau at the end of the protocol and was greater in participants with low motor threshold. Participants receiving reverse-ccPAS (i.e., M1-to-PMv) showed a trend toward inhibition. Our study highlights the facilitatory and inhibitory modulations that occur during ccPAS administration and suggest that online MEP monitoring could provide insights into the malleability of the motor system and protocol’s effectiveness. Our findings open interesting prospects about ccPAS potential optimization in experimental and clinical settings

Realistic modeling of mesoscopic ephaptic coupling in the human brain

Altres ajuts: The National Institutes of Health (R01HD069776, R01NS073601, R21MH099196, R21 NS082870, R21 NS085491, R21HD07616)Several decades of research suggest that weak electric fields may influence neural processing, including those induced by neuronal activity and proposed as a substrate for a potential new cellular communication system, i.e., ephaptic transmission. Here we aim to model mesoscopic ephaptic activity in the human brain and explore its trajectory during aging by characterizing the electric field generated by cortical dipoles using realistic finite element modeling. Extrapolating from electrophysiological measurements, we first observe that modeled endogenous field magnitudes are comparable to those in measurements of weak but functionally relevant self-generated fields and to those produced by noninvasive transcranial brain stimulation, and therefore possibly able to modulate neuronal activity. Then, to evaluate the role of these fields in the human cortex in large MRI databases, we adapt an interaction approximation that considers the relative orientation of neuron and field to estimate the membrane potential perturbation in pyramidal cells. We use this approximation to define a simplified metric (EMOD1) that weights dipole coupling as a function of distance and relative orientation between emitter and receiver and evaluate it in a sample of 401 realistic human brain models from healthy subjects aged 16-83. Results reveal that ephaptic coupling, in the simplified mesoscopic modeling approach used here, significantly decreases with age, with higher involvement of sensorimotor regions and medial brain structures. This study suggests that by providing the means for fast and direct interaction between neurons, ephaptic modulation may contribute to the complexity of human function for cognition and behavior, and its modification across the lifespan and in response to pathology

Individual and sex-related differences in pain and relief responsiveness are associated with differences in resting-state functional networks in healthy volunteers

Pain processing is associated with neural activity in a number of widespread brain regions. Here, we investigated whether functional connectivity at rest between these brain regions is associated with individual and sex-related differences in thermal pain and relief responsiveness. Twenty healthy volunteers (ten females) were scanned with functional magnetic resonance imaging in resting conditions. Half an hour after scanning, we administered thermal pain on the back of their right hand and collected pain and relief ratings in two separate runs of twelve stimuli each. Across the whole group, mean pain ratings were associated with decreased connectivity at rest between brain regions belonging to the default mode and the visual resting-state network. In men, pain measures correlated with increased connectivity within the visual resting-state network. In women, in contrast, decreased connectivity between this network and parietal and prefrontal brain regions implicated in affective cognitive control were associated with both pain and relief ratings. Our findings indicate that the well documented individual variability and sex differences in pain sensitivity may be explained, at least in part, by network dynamics at rest in these brain regions

Interaction between Neuroanatomical and Psychological Changes after Mindfulness-Based Training

Several cross-sectional studies have documented neuroanatomical changes in individuals with a long history of meditation, while a few evidences are available about the interaction between neuroanatomical and psychological changes even during brief exposure to meditation. Here we analyzed several morphometric indexes at both cortical and subcortical brain level, as well as multiple psychological dimensions, before and after a brief -8 weeks- Mindfulness Based Stress Reduction (MBSR) training program, in a group of 23 meditation naïve-subjects compared to age-gender matched subjects. We found a significant cortical thickness increase in the right insula and the somatosensory cortex of MBSR trainees, coupled with a significant reduction of several psychological indices related to worry, state anxiety, depression and alexithymia. Most importantly, an interesting correlation between the increase in right insula thickness and the decrease in alexithymia levels during the MBSR training were observed. Moreover, a multivariate pattern classification approach allowed to identify a cluster of regions more responsive to MBSR training across subjects. Taken together, these findings documented the significant impact of a brief MBSR training on brain structures, as well as stressing the idea of MBSR as a valuable tool for alexithymia modulation, also originally providing a plausible neurobiological evidence of a major role of right insula into mediating the observed psychological changes

Psychological and Brain Connectivity Changes Following Trauma-Focused CBT and EMDR Treatment in Single-Episode PTSD Patients

Among the different therapeutic alternatives for post-traumatic stress disorder (PTSD), Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT) and Eye Movement Desensitization and Reprocessing (EMDR) Therapy have shown promising results in helping patients cope with PTSD symptoms. However, given the different theoretical and methodological substrate of TF-CBT and EMDR, a potentially different impact on the brain for the two interventions could be hypothesized, as well as an interaction between trauma-specific PTSD symptomatology and response to a given psychotherapy. In this study, we monitored psychological and spontaneous functional connectivity fMRI patterns in two groups of PTSD patients who suffered by the same traumatic event (i.e., natural disaster), before and after a cycle of psychotherapy sessions based on TF-CBT and EMDR. Thirty-seven (37) PTSD patients were enrolled from a larger sample of people exposed to a single, acute psychological stress (i.e., 2002 earthquake in San Giuliano di Puglia, Italy). Patients were randomly assigned to TF-CBT (n = 14) or EMDR (n = 17) psychotherapy. Clinical assessment was performed using the Clinician-Administered PTSD Scale (CAPS), the Davidson Trauma Scale (DTS) and the Work and Social Adjustment Scale (WSAS), both at baseline and after treatment. All patients underwent a fMRI data acquisition session before and after treatment, aimed at characterizing their functional connectivity (FC) profile at rest, as well as potential connectivity changes associated with the clinical impact of psychotherapy. Both EMDR and TF-CBT induced statistically significant changes in clinical scores, with no difference in the clinical impact of the two treatments. Specific changes in FC correlated with the improvement at the different clinical scores, and differently for EMDR and TF-CBT. However, a similarity in the connectivity changes associated with changes in CAPS in both groups was also observed. Specifically, changes at CAPS in the entire sample correlated with an (i) increase in connectivity between the bilateral superior medial frontal gyrus and right temporal pole, and a (ii) decrease in connectivity between left cuneus and left temporal pole. Results point to a similar, beneficial psychological impact of EMDR and TF-CBT for treatment of natural-disaster PTSD patients. Neuroimaging data suggest a similar neurophysiological substrate for clinical improvement following EMDR and TF-CBT, involving changes affecting bilateral temporal pole connectivity

Greater cognitive reserve is related to lower cortical excitability in healthy cognitive aging, but not in early clinical Alzheimer’s disease

ObjectiveTo investigate the relationship between cortico-motor excitability and cognitive reserve (CR) in cognitively unimpaired older adults (CU) and in older adults with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD).MethodsData were collected and analyzed from 15 CU and 24 amyloid-positive AD participants aged 50–90 years. A cognitive reserve questionnaire score (CRQ) assessed education, occupation, leisure activities, physical activities, and social engagement. Cortical excitability was quantified as the average amplitude of motor evoked potentials (MEP amplitude) elicited with single-pulse transcranial magnetic stimulation delivered to primary motor cortex. A linear model compared MEP amplitudes between groups. A linear model tested for an effect of CRQ on MEP amplitude across all participants. Finally, separate linear models tested for an effect of CRQ on MEP amplitude within each group. Exploratory analyses tested for effect modification of demographics, cognitive scores, atrophy measures, and CSF measures within each group using nested regression analysis.ResultsThere was no between-group difference in MEP amplitude after accounting for covariates. The primary model showed a significant interaction term of group*CRQ (R2adj = 0.18, p = 0.013), but no main effect of CRQ. Within the CU group, higher CRQ was significantly associated with lower MEP amplitude (R2adj = 0.45, p = 0.004). There was no association in the AD group.ConclusionLower cortico-motor excitability is related to greater CRQ in CU, but not in AD. Lower MEP amplitudes may reflect greater neural efficiency in cognitively unimpaired older adults. The lack of association seen in AD participants may reflect disruption of the protective effects of CR. Future work is needed to better understand the neurophysiologic mechanisms leading to the protective effects of CR in older adults with and without neurodegenerative disorders

Transcranial random noise stimulation does not improve behavioral and neurophysiological measures in patients with subacute Vegetative-Unresponsive Wakefulness State (VS-UWS)

Background: The absence of efficient treatments capable to promote central nervous system recovery in patients in vegetative state (VS) due to a severe acquired brain injury highlights the need of exploring alternative neuromodulatory treatments that can lead to neurobehavioral gains. Some encouraging preliminary observations suggest that transcranial direct current stimulation could be effective in disorders of consciousness (DoC) patients, especially when applied on the dorsolateral prefrontal cortex (DLPFC) in patients with minimally conscious state (MCS) but not in those with VS. Objective: The primary aim of the present study was to verify if the application of transcranial random noise stimulation (tRNS) on the DLPFC might favor improvements of consciousness recovery in subacute VS-UWS. Methods: Nine patients with DoC due to traumatic brain injury (n D 1), anoxia (n D 3), and vascular damage (n D 5), have undergone a randomized, double-blind, shamcontrolled, neuromodulatory trial with tRNS of bilateral DLPFC. All patients were in a post-acute phase and the DoC onset ranged from 30 days to 4 months. The diagnosis of DoC was based on internationally established criteria from the Multi-Society Task Force on PVS, and classified as VS or MCS using the JFK Coma Recovery Scale- Revised scores (CRS-R). We used CRS-R, Synek Scale, Ad-Hoc semi-quantitative scale and the Clinical Global Impression-Improvement scale to measure behavioral and electrophysiological changes during tRNS intervention. All patients were also treated with daily conventional rehabilitation treatment. Results: No significant differences emerged between active and sham groups regarding improvements of level of consciousness, as well as on electroencephalographic data. Only one patient showed emergence from VS-UWS, evolving from VS to MCS after the tRNS stimulation, at a distance of 3 weeks from the enrolment into the study. Conclusion: Repeated applications of tRNS of the DLPFC, even if applied in a subacute phase of VS-UWS state, did not modify behavioral and neurophysiological outcomes differently than sham stimulation

Age of Insomnia Onset Correlates with a Reversal of Default Mode Network and Supplementary Motor Cortex Connectivity

Insomnia might occur as result of increased cognitive and physiological arousal caused by acute or long acting stressors and associated cognitive rumination. This might lead to alterations in brain connectivity patterns as those captured by functional connectivity fMRI analysis, leading to potential insight about primary insomnia (PI) pathophysiology as well as the impact of long-term exposure to sleep deprivation. We investigated changes of voxel-wise connectivity patterns in a sample of 17 drug-naïve PI patients and 17 age-gender matched healthy controls, as well as the relationship between brain connectivity and age of onset, illness duration, and severity. Results showed a significant increase in resting-state functional connectivity of the bilateral visual cortex in PI patients, associated with decreased connectivity between the visual cortex and bilateral temporal pole. Regression with clinical scores originally unveiled a pattern of increased local connectivity as measured by intrinsic connectivity contrast (ICC), specifically resembling the default mode network (DMN). Additionally, age of onset was found to be correlated with the connectivity of supplementary motor area (SMA), and the strength of DMN←→SMA connectivity was significantly correlated with both age of onset (R2 = 41%) and disease duration (R2 = 21%). Chronic sleep deprivation, but most importantly early insomnia onset, seems to have a significant disruptive effect over the physiological negative correlation between DMN and SMA, a well-known fMRI marker of attention performance in humans. This suggests the need for more in-depth investigations on the prevention and treatment of connectivity changes and associated cognitive and psychological deficits in PI patients

Peculiarities of Functional Connectivity—including Cross-Modal Patterns—in Professional Karate Athletes: Correlations with Cognitive and Motor Performances

Professional karate is a sport activity requiring both physical and psychological skills that have been associated with a better "global neural efficacy." By means of resting state functional magnetic resonance imaging (rs-fMRI), we investigated the neural correlates of cognitive and kinematic abilities in a group of 14 professional karateka and 14 heathy matched controls. All subjects underwent an extensive cognitive test battery for the identification of individual multidimensional cognitive profile and rs-fMRI scans investigating functional connectivity (FC). Moreover, kinematic performances in athletes were quantified by the Ergo-Mak, an integrated system developed for measuring motor reactivity, strength, and power of athletic gestures. Karateka performed significantly better than controls in the visual search task, an ability linked with increased positive correlations in FC between the right superior parietal lobe and bilateral occipital poles. Kinematic performances of athletic feats were sustained by increased positive correlations between subcortical (cerebellum and left thalamus) and cortical (inferior frontal cortex, superior parietal cortex, superior temporal cortex) regions. An unexpected FC increase between auditory and motor-related areas emerged in karateka, possibly reflecting a cross-modal coupling due to the continuous exposure to either internal or external auditory cues, positing this sensory channel as a possible target for novel training strategies. Results represent a further step in defining brain correlates of "neural efficiency" in these athletes, whose brain can be considered a model of continuous plastic train-related adaptation

Personalised, image-guided, noninvasive brain stimulation in gliomas : Rationale, challenges and opportunities

Malignant brain tumours are among the most aggressive human cancers, and despite intensive efforts made over the last decades, patients' survival has scarcely improved. Recently, high-grade gliomas (HGG) have been found to be electrically integrated with healthy brain tissue, a communication that facilitates tumour mitosis and invasion. This link to neuronal activity has provided new insights into HGG pathophysiology and opened prospects for therapeutic interventions based on electrical modulation of neural and synaptic activity in the proximity of tumour cells, which could potentially slow tumour growth. Noninvasive brain stimulation (NiBS), a group of techniques used in research and clinical settings to safely modulate brain activity and plasticity via electromagnetic or electrical stimulation, represents an appealing class of interventions to characterise and target the electrical properties of tumour-neuron interactions. Beyond neuronal activity, NiBS may also modulate function of a range of substrates and dynamics that locally interacts with HGG (e.g., vascular architecture, perfusion and blood-brain barrier permeability). Here we discuss emerging applications of NiBS in patients with brain tumours, covering potential mechanisms of action at both cellular, regional, network and whole-brain levels, also offering a conceptual roadmap for future research to prolong survival or promote wellbeing via personalised NiBS interventions