Afferent Inhibition Research Articles

Locomotor Muscle Afferent Inhibition Augments Activation Of Locomotor Muscles In Heart Failure Patients During Exercise

Exercise intolerance is a hallmark feature of heart failure with reduced ejection fraction (HFrEF). Locomotor muscle afferent feedback contributes to exercise intolerance in patients with HFrEF. Locomotor muscle afferent inhibition via intrathecal fentanyl, compared to the sham condition (SHAM), results in increased peak workload, cardiac output, and leg oxygen delivery during maximal exercise. To date, the impact of locomotor muscle afferent feedback inhibition on locomotor muscle activation responses during exercise in patients with HFrEF have not been investigated. PURPOSE: To determine the effect of intrathecal fentanyl on vastus lateralis (VL) muscle activation during incremental exercise in patients with HFrEF. METHODS: Patients with HFrEF (n = 7, EF: 35 ± 13%, age: 60 ± 9 yrs, BMI 28.7 ± 5.5 kg/m2) performed an incremental cycle test to task failure with lumbar intrathecal fentanyl (FENT) or SHAM (in randomized order). Electromyography (EMG) of the VL was measured and the root-mean square (RMS) of 10 contractions were averaged at 30 W, 50 W, 70 W, and peak workload. Changes in RMS were normalized as a percent of the SHAM response (unloaded = 0%; peak workload = 100%). RESULTS: Peak workload was significantly greater with FENT compared to SHAM (129 ± 30 vs. 114 ± 31 W, p = 0.04). VL RMS was not different at 30 W between FENT and SHAM (FENT: 44 ± 22 vs. SHAM: 17 ± 33%, p = 0.06). However, VL RMS was greater with FENT compared to SHAM at 50 W (FENT: 82 ± 61 vs. SHAM: 31 ± 24%), 70 W (FENT: 96 ± 56 vs. SHAM: 45 ± 29%), and peak workload (FENT: 167 ± 55 vs. SHAM: 92 ± 10%) (all, p < 0.04). There was no significant relationship between the change in peak workload and VL RMS with FENT with both normalized as a percent of the SHAM response (p = 0.09). CONCLUSION: These data suggest that locomotor muscle afferent feedback may contribute to exercise intolerance via inhibition of locomotor muscle activation during exercise in patients with HFrEF.

TU-136. Short latency afferent inhibition and facilitation in the motor cortex of patients with progressive myoclonus epilepsy type 1 (EPM1)

TU-136. Short latency afferent inhibition and facilitation in the motor cortex of patients with progressive myoclonus epilepsy type 1 (EPM1)

Glutamate inputs from the laterodorsal tegmental nucleus to the ventral tegmental area are essential for the induction of cocaine sensitization in male mice.

Drug-induced potentiation of ventral tegmental area (VTA) glutamate signaling contributes critically to the induction of sensitization - an enhancement in responding to a drug following exposure which is thought to reflect neural changes underlying drug addiction. The laterodorsal tegmental nucleus (LDTg) provides one of several sources of glutamate input to the VTA. We used optogenetic techniques to test either the role of LDTg glutamate cells or their VTA afferents in the development of cocaine sensitization in male VGluT2::Cre mice. These were inhibited using halorhodopsin during each of five daily cocaine exposure injections. The expression of locomotor sensitization was assessed following a cocaine challenge injection 1-week later. The locomotor sensitization seen in control mice was absent in male mice subjected to inhibition of LDTg-VTA glutamatergic circuitry during cocaine exposure. As sensitization of nucleus accumbens (NAcc) dopamine (DA) overflow is also induced by this drug exposure regimen, we used microdialysis to measure NAcc DA overflow on the test for sensitization. Consistent with the locomotor sensitization results, inhibition of LDTg glutamate afferents to the VTA during cocaine exposure prevented the sensitization of NAcc DA overflow observed in control mice. These data identify the LDTg as the source of VTA glutamate critical for the development of cocaine sensitization in male mice. Accordingly, the LDTg may give rise to the synapses in the VTA at which glutamatergic plasticity, known to contribute to the enhancement of addictive behaviors, occurs.

Specific sensorimotor interneuron circuits are sensitive to cerebellar-attention interactions.

Background: Short latency afferent inhibition (SAI) provides a method to investigate mechanisms of sensorimotor integration. Cholinergic involvement in the SAI phenomena suggests that SAI may provide a marker of cognitive influence over implicit sensorimotor processes. Consistent with this hypothesis, we previously demonstrated that visual attention load suppresses SAI circuits preferentially recruited by anterior-to-posterior (AP)-, but not posterior-to-anterior (PA)-current induced by transcranial magnetic stimulation. However, cerebellar modulation can also modulate these same AP-sensitive SAI circuits. Yet, the consequences of concurrent cognitive and implicit cerebellar influences over these AP circuits are unknown.Objective: We used cerebellar intermittent theta-burst stimulation (iTBS) to determine whether the cerebellar modulation of sensory to motor projections interacts with the attentional modulation of sensory to motor circuits probed by SAI.Methods: We assessed AP-SAI and PA-SAI during a concurrent visual detection task of varying attention load before and after cerebellar iTBS.Results: Before cerebellar iTBS, a higher visual attention load suppressed AP-SAI, but not PA-SAI, compared to a lower visual attention load. Post-cerebellar iTBS, the pattern of AP-SAI in response to visual attention load, was reversed; a higher visual attention load enhanced AP-SAI compared to a lower visual attention load. Cerebellar iTBS did not affect PA-SAI regardless of visual attention load.Conclusion: These findings suggest that attention and cerebellar networks converge on overlapping AP-sensitive circuitry to influence motor output by controlling the strength of the afferent projections to the motor cortex. This interaction has important implications for understanding the mechanisms of motor performance and learning.

Older adults' episodic memory is related to a neurophysiological marker of brain cholinergic activity.

Episodic memory is vulnerable to aging and may be influenced by age-related decline in the neurotransmitter acetylcholine. We probed this relation using a novel, minimally invasive transcranial magnetic stimulation marker of brain acetylcholine: short-latency afferent inhibition (SAI). We used neuropsychological testing to construct a composite score of episodic memory in N = 19 community-dwelling older adults, and stratified older adults into Higher- (N = 9) versus Lower-memory (N = 10) groups before SAI. The Higher-memory group showed significantly stronger SAI than the Lower-memory group, indicating an association between higher brain acetylcholine levels and better episodic memory. The two memory groups were equivalent in the potential confounds of age, education, mood, subjective sleep quality, and executive function. These data converge with others to suggest that episodic memory is related to acetylcholine in older adults. This relation should be further investigated, especially with pharmacology and neuroimaging.

Suppression of perioperative stress response in elective abdominal surgery: A randomized comparison between dexmedetomidine and epidural block.

Stress response after surgery induces local and systemic inflammation which may be detrimental if it goes unchecked. Blockade of afferent neurons or inhibition of hypothalamic function may mitigate the stress response. A total of 50 consenting adult ASA I/II patients undergoing elective abdominal surgery were randomized to receive either dexmedetomidine (Group D) or epidural bupivacaine (Group E) in addition to balanced general anesthesia. Laparoscopic surgery, contraindications to epidural administration, history of psychiatric disorders, obesity (BMI >30 kg/m2), on beta blockers or continuous steroid therapy for >5 days over last 1 year, and known case of endocrine abnormalities or malignancy were excluded. Serum cortisol, blood glucose, and blood urea were estimated. Hemodynamic parameters, total dose of dexmedetomidine, bupivacaine, emergence characteristics, and analgesic consumption over 24 h postoperatively were recorded. Statistical comparisons were done using Student's t-test, repeated measure analysis of variance followed by Dunnett's test, generalized linear model and Chi-square/Fisher's exact test. A P value <0.05 was considered significant. Serum cortisol levels were significantly lower in group E than group D 24 h after surgery (P = 0.029). Intraoperative and postoperative glucose level was lower in group E compared with group D. Time to request of first rescue analgesic was longer in group E than group D (P = 0.040). There was no significant difference between the number of doses of paracetamol required in the postoperative period (P = 0.198). Epidural bupivacaine was more effective than intravenous dexmedetomidine for suppression of neuroendocrine and metabolic response to surgery. Dexmedetomidine provided better hemodynamic stability at the time of noxious stimuli and postoperatively.

Mesodiencephalic junction GABAergic inputs are processed separately from motor cortical inputs in the basilar pons

SummaryThe basilar pontine nuclei (bPN) are known to receive excitatory input from the entire neocortex and constitute the main source of mossy fibers to the cerebellum. Various potential inhibitory afferents have been described, but their origin, synaptic plasticity, and network function have remained elusive. Here we identify the mesodiencephalic junction (MDJ) as a prominent source of monosynaptic GABAergic inputs to the bPN. We found no evidence that these inputs converge with motor cortex (M1) inputs at the single neuron or at the local network level. Tracing the inputs to GABAergic MDJ neurons revealed inputs to these neurons from neocortical areas. Additionally, we observed little short-term synaptic facilitation or depression in afferents from the MDJ, enabling MDJ inputs to carry sign-inversed neocortical inputs. Thus, our results show a prominent source of GABAergic inhibition to the bPN that could enrich input to the cerebellar granule cell layer.

Short-Latency Afferent Inhibition Correlates with Stage of Disease in Parkinson's Patients.

Sensory-motor decoupling at the cortical level involving cholinergic circuitry has also been reported in Parkinson's Disease (PD). Short-latency afferent inhibition (SAI) is a transcranial magnetic stimulation (TMS) paradigm that has been used previously to probe cortical cholinergic circuits in well-characterised subgroups of patients with PD. In the current study, we compared SAI in a cohort of PD patients at various stages of disease and explored correlations between SAI and various clinical measures of disease severity. The modified Hoehn and Yahr (H&Y) scale was used to stage disease in 22 patients with PD. Motor and cognitive function were assessed using the MDS-UPDRS (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale) part III and MoCA (Montreal Cognitive Assessment) score, respectively. Objective gait assessment was performed using an electronic walkway (GAITRite®). SAI was measured as the average percentage inhibition of test motor-evoked potentials (MEPs) conditioned by electrical stimulation of the contralateral median nerve at the wrist. SAI was significantly reduced in patients with advanced PD (H&Y stage 3) compared to early PD patients (H&Y stage 1) on pairwise comparison. The visuospatial executive function and orientation domains of cognition demonstrated significant negative associations with SAI. Cortical sensory-motor integration is progressively diminished as disease progresses. The observation that a reduction in SAI is associated with a reduction in cognitive function possibly reflects the progressive involvement of cortical cholinergic circuits in PD with increasing motor stage. Future longitudinal studies are necessary to confirm this preliminary result.

The recent history of afferent stimulation modulates corticospinal excitability

BackgroundTranscranial magnetic stimulation (TMS) is widely used to probe corticospinal excitability and fast sensorimotor integration in the primary motor hand area (M1-HAND). A conditioning electrical stimulus, applied to the contralateral hand, can suppress the motor evoked potential (MEP) elicited by TMS of M1-HAND when the afferent stimulus arrives in M1-HAND at the time of TMS. The magnitude of this short-latency afferent inhibition (SAI) is expressed as the ratio between the conditioned and unconditioned MEP amplitude. Objective/HypothesisWe hypothesized that corticospinal excitability and SAI are influenced by the recent history of peripheral electrical stimulation. MethodsIn twenty healthy participants, we recorded MEPs from the right first dorsal interosseus muscle. MEPs were evoked by single-pulse TMS of the left M1-HAND alone (unconditioned TMS) or by TMS preceded by electrical stimulation of the right index finger (“homotopic” conditioning) or little finger (“heterotopic” conditioning). The three conditions were either pseudo-randomly intermixed or delivered in blocks in which a single condition was repeated five or ten times. MEP amplitudes and SAI magnitudes were compared using linear mixed-effect models and one-way ANOVAs. ResultsAll stimulation protocols consistently produced SAI, which was stronger after homotopic stimulation. Randomly intermingling the three stimulation conditions reduced the relative magnitude of homotopic and heterotopic SAI as opposed to blocked stimulation. The apparent attenuation of SAI was caused by a suppression of the unconditioned but not the conditioned MEP amplitude during the randomly intermixed pattern. Conclusion(s): The recent history of afferent stimulation modulates corticospinal excitability. This “history effect” impacts on the relative magnitude of SAI depending on how conditioned and unconditioned responses are intermixed and needs to be taken into consideration when probing afferent inhibition and corticospinal excitability.

Increasing Brain Gamma Activity Improves Episodic Memory and Restores Cholinergic Dysfunction in Alzheimer's Disease.

ObjectiveThis study aimed to assess whether non‐invasive brain stimulation with transcranial alternating current stimulation at gamma‐frequency (γ‐tACS) applied over the precuneus can improve episodic memory and modulate cholinergic transmission by modulating cerebral rhythms in early Alzheimer's disease (AD).MethodsIn this randomized, double‐blind, sham controlled, crossover study, 60 AD patients underwent a clinical and neurophysiological evaluation including assessment of episodic memory and cholinergic transmission pre and post 60 minutes treatment with γ‐tACS targeting the precuneus or sham tACS. In a subset of 10 patients, EEG analysis and individualized modelling of electric field distribution were carried out. Predictors to γ‐tACS efficacy were evaluated.ResultsWe observed a significant improvement in the Rey Auditory Verbal Learning (RAVL) test immediate recall (p < 0.001) and delayed recall scores (p < 0.001) after γ‐tACS but not after sham tACS. Face‐name associations scores improved with γ‐tACS (p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission, increased only after γ‐tACS (p < 0.001). ApoE genotype and baseline cognitive impairment were the best predictors of response to γ‐tACS. Clinical improvement correlated with the increase in gamma frequencies in posterior regions and with the amount of predicted electric field distribution in the precuneus.InterpretationPrecuneus γ‐tACS, able to increase γ‐power activity on the posterior brain regions, showed a significant improvement of episodic memory performances, along with restoration of intracortical excitability measures of cholinergic transmission. Response to γ‐tACS was dependent on genetic factors and disease stage. ANN NEUROL 2022;92:322–334

Investigation of selective vagal afferents subserving baroreflex function and blood pressure control: implications for understanding and alleviating hypertension

Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors (BRs) that apprise the brain of blood volume and pressure within the carotid sinus and aortic arch. Here, we test the overall hypothesis that neurons within the nodose ganglia that express the angiotensin type 1a receptor (referred to as NDGAT1aR) serve as BR that undergo plasticity during chronic elevations in blood pressure (BP). Towards this end, mice that express Cre‐recombinase at the AT1aR locus were delivered a Cre‐dependent AAV to express tdTomato within NDGAT1aR. These studies revealed that NDGAT1aR receive input from the aortic arch and carotid sinus, project to the caudal nucleus of the solitary tract (cNTS), and synthesize mechanosensitive ion channels, Piezo‐1/‐2. To determine whether NDGAT1aR couple their firing to elevated BP, we generated mice with the expression of the fluorescent Ca2+ indicator, GCaMP6s, directed to the AT1aR locus. Two‐photon (2P) intravital imaging revealed that phenylephrine (PE; i.v.) significantly increased GCaMP6s fluorescence within NDGAT1aR. To determine if optogenetic perturbation of NDGAT1aR at their soma or axon terminals within the cNTS affect the baroreflex, we directed the expression of excitatory (channelrhodpsin2; ChR2) or inhibitory (halorhodopsin; Halo) opsins to the AT1aR locus. Optical excitation of NDGAT1aR at their soma or axons terminals in the cNTS, elicited robust and frequency‐dependent decreases in BP and heart rate. Conversely, optical inhibition of afferents in the cNTS originating from NDGAT1aR blunted pressor responses to PE. The implication is that NDGAT1aR are sufficient and necessary to elicit appropriate compensatory responses to vascular mechanosensation induced by vasoconstriction. Opsin‐ or GCaMP6s‐expressing mice were then subjected to the DOCA‐salt model of hypertension. Optical excitation elicited hypotensive and bradycardic responses; however, the duration of these effects was altered, consistent with hypertension‐induced impairment of BR. Similarly, the increased GCaMP6s fluorescence observed after administration of PE was significantly delayed in mice that were subjected to DOCA‐salt or chronic delivery of angiotensin II. Finally, AT1aR‐flox mice were delivered AAV expressing Cre and/or tdTomato into the nodose ganglia to probe the function of AT1aR(s) themselves, in mediating the baroreflex. Preliminary results indicate deleting AT1aR(s) from the nodose ganglia alters pressor responses to vasoactive drugs. Collectively, these results reveal the structure and function of NDGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension.

Sensorimotor inhibition during emotional processing

Visual processing of emotional stimuli has been shown to engage complex cortical and subcortical networks, but it is still unclear how it affects sensorimotor integration processes. To fill this gap, here, we used a TMS protocol named short-latency afferent inhibition (SAI), capturing sensorimotor interactions, while healthy participants were observing emotional body language (EBL) and International Affective Picture System (IAPS) stimuli. Participants were presented with emotional (fear- and happiness-related) or non-emotional (neutral) EBL and IAPS stimuli while SAI was tested at 120 ms and 300 ms after pictures presentation. At the earlier time point (120 ms), we found that fear-related EBL and IAPS stimuli selectively enhanced SAI as indexed by the greater inhibitory effect of somatosensory afferents on motor excitability. Larger early SAI enhancement was associated with lower scores at the Behavioural Inhibition Scale (BIS). At the later time point (300 ms), we found a generalized SAI decrease for all kind of stimuli (fear, happiness or neutral). Because the SAI index reflects integrative activity of cholinergic sensorimotor circuits, our findings suggest greater sensitivity of such circuits during early (120 ms) processing of threat-related information. Moreover, the correlation with BIS score may suggest increased attention and sensory vigilance in participants with greater anxiety-related dispositions. In conclusion, the results of this study show that sensorimotor inhibition is rapidly enhanced while processing threatening stimuli and that SAI protocol might be a valuable option in evaluating emotional-motor interactions in physiological and pathological conditions.

Sleep restriction alters cortical inhibition in migraine: A transcranial magnetic stimulation study

ObjectiveMigraine is a primary headache disorder with a well-known association with insufficient sleep. However, both the underlying pathophysiology of the disease and the relationship with sleep is still unexplained. In this study, we apply transcranial magnetic stimulation to investigate possible mechanisms of insufficient sleep in migraine. MethodsWe used a randomised, blinded crossover design to examine 46 subjects with migraine during the interictal period and 29 healthy controls. Each subject underwent recordings of cortical silent period, short- and long-interval intracortical inhibition, intracortical facilitation and short-latency afferent inhibition after both two nights of habitual eight-hour sleep and two nights of restricted four-hour sleep. ResultsWe found reduced cortical silent period duration after sleep restriction in interictal migraineurs compared to controls (p = 0.046). This effect was more pronounced for non-sleep related migraine (p = 0.002) and migraine with aura (p = 0.017). The sleep restriction effect was associated with ictal symptoms of hypersensitivity such as photophobia (p = 0.017) and overall silent period was associated with premonitory dopaminergic symptoms such as yawning (p = 0.034). ConclusionsSleep restriction reduces GABAergic cortical inhibition during the interictal period in individuals with migraine. SignificanceSleep related mechanisms appear to affect the pathophysiology of migraine and may differentiate between migraine subgroups.

Neurophysiological and behavioural correlates of ocrelizumab therapy on manual dexterity in patients with primary progressive multiple sclerosis

BackgroundHand dexterity impairment is a key feature of disability in people with primary progressive multiple sclerosis (PPMS). So far, ocrelizumab, a recombinant humanized monoclonal antibody that selectively depletes CD20-expressing B cells, is the only therapy approved for PPMS and recent analysis reported its ability to reduce the risk of upper limb disability progression. However, the neural mechanisms underlying hand impairment in PPMS and the brain networks behind the effect of ocrelizumab on manual dexterity are not fully understood.ObjectiveMain aims of our study were: (i) to investigate neurophysiological and behavioural correlates of hand function impairment in subjects with PPMS, and (ii) to use neurophysiologic and behavioural measures to track the effects of ocrelizumab therapy on manual dexterity.MethodsSeventeen PPMS patients and 17 healthy-controls underwent routine neurophysiological protocols assessing the integrity of cortico-spinal and somatosensory pathways and advanced transcranial magnetic stimulation (TMS) protocols evaluating inhibitory (short and long interval intracortical inhibition, short-latency afferent inhibition) and facilitatory (motor thresholds, intracortical facilitation, short-interval intracortical facilitation) circuits in the primary motor cortex. All subjects also underwent behavioural analysis of hand dexterity by means of nine-hole peg test and finger movement analysis, and hand strength with handgrip and three-point pinch test. Neurophysiological and clinical assessments of hand functionality were also performed after 1 year of ocrelizumab therapy.ResultsAt baseline PPMS patients displayed a significant impairment of hand dexterity and strength compared to healthy controls (all p < 0.03). Neurophysiological study disclosed prolonged latencies of standard somatosensory and motor evoked potentials (all p < 0.025) and an overall reduction of intracortical excitability at TMS protocols, involving both excitatory and inhibitory circuits. Importantly, hand dexterity impairment, indexed by delayed 9HPT, correlated with TMS protocols investigating cortical sensorimotor integration (short-latency afferent inhibition, SAI), p = 0.009. Both parameters, 9HPT (p = 0.01) and SAI (p = 0.01), displayed a significant improvement after 1 year of therapy with ocrelizumab.ConclusionIntracortical sensorimotor networks are involved in hand dexterity dysfunction of PPMS. Ocrelizumab therapy displays a beneficial effect on hand dexterity impairment most likely through intracortical networks implicated in fast sensorimotor integration.

P 84 Altered sensorimotor integration of afferent inhibition in patients with complex regional pain syndrome

Introduction: The complex regional pain syndrome (CRPS) is a chronic pain condition which frequently results in sensorimotor dysfunction of the affected limb. With respect to pathophysiology an impaired interaction in sensorimotor cortex has been hypothesized 1 . Sensorimotor interactions can be assessed through transcranial magnetic stimulation (TMS) that is preceded by an electrical stimulation of peripheral motor or sensory nerves (short/ long afferent inhibition; SAI/LAI). Previous studies revealed only minor alterations of LAI using peripheral motor stimulation in CRPS 2 . This study uses a more comprehensive assessment of SAI and LAI, induced by motor and sensory peripheral stimulation, to assess interaction of the sensorimotor system in CRPS. Methods : 13 unilateral upper limb affected patients with CRPS (9 females, 54 ± 17.8 years) and 11 controls (HCs; 8 females, 52± 18.3 years) received TMS on either hemisphere. SAI and LAI were induced by a motor (m_) or sensory (s_) median nerve stimulation preceded by TMS with 20ms (m_SAI) and 200ms (m_LAI) or 23ms (s_SAI) and 203ms (s_LAI), respectively 3 . Twenty paired and single TMS stimuli were randomly applied for each condition. Results: Pain levels were 5.1±1.5/10 at rest and 7.4±2.1/10 during movements. ANOVA revealed a significant group effect for patients vs. HCs on the affected side (F=2.2, p=0.048). Post hoc tests were corrected for multiple comparisons and showed reduced inhibition in patients after sensory stimulation (s_SAI: t=-2.51, p=0.04; s_LAI: t=-2.53 p=0.038) and motor stimulation with ISI 200ms (m_LAI: t=-2.62, p=0.032). Afferent sensorimotor inhibition was lower in patients with longer disease duration (r=-0.66, p=0.014). Discussion: We demonstrate altered sensorimotor integration of afferent inhibition in CRPS. Since afferent inhibition after sensory stimulation is thought to be mediated via interconnections especially between Brodmann area 3b of somatosensory and the motor cortex, our results complement existing literature about maladaptive cortical plasticity of these regions in CRPS 4,5 . Impairment in LAI, that is thought to involve higher-order somatosensory cortical areas and the posterior parietal cortex is in line with existing literature on chronic pain 2,4 . Future longitudinal investigation should evaluate intra- and intercortical sensorimotor integration systematically in CRPS to better understand their impact in development of sensorimotor symptoms. Literature: 1 Harris AJ. Cortical origins of pathological pain. Lancet 1999. 2 Morgante et al. Normal sensorimotor plasticity in complex regional pain syndrome with fixed posture of the hand. Mov Disord. 2017. 3 Sailer A, et al. Brain. 2003. 4 Chen et al. Modulation of motor cortex excitability by median nerve and digit stimulation. Exp Brain Res. 1999. 5 Pfannmöller et al. Investigations on maladaptive plasticity in the sensorimotor cortex of unilateral upper limb CRPS I patients. RNN. 2019.

Anodal Transcranial Direct Current Stimulation Could Modulate Cortical Excitability and the Central Cholinergic System in Akinetic Rigid-Type Parkinson's Disease: Pilot Study.

BackgroundTranscranial direct current stimulation (tDCS) is a non-invasive technique that has been widely studied as an alternative treatment for Parkinson's disease (PD). However, its clinical benefit remains unclear. In this study, we aimed to investigate the effect of tDCS on the central cholinergic system and cortical excitability in mainly akinetic rigid-type patients with PD.MethodsIn total, 18 patients with PD were prospectively enrolled and underwent 5 sessions of anodal tDCS on the M1 area, which is on the contralateral side of the dominant hand. We excluded patients with PD who had evident resting tremor of the hand to reduce the artifact of electrophysiologic findings. We compared clinical scales reflecting motor, cognitive, and mood symptoms between pre- and post-tDCS. Additionally, we investigated the changes in electrophysiologic parameters, such as short latency afferent inhibition (SAI) (%), which reflects the central cholinergic system.ResultsThe United Parkinson's Disease Rating Scale Part 3 (UPDRS-III), the Korean-Montreal Cognitive Assessment (MoCA-K), and Beck Depression Inventory (BDI) scores were significantly improved after anodal tDCS (p < 0.01, p < 0.01, and p < 0.01). Moreover, motor evoked potential amplitude ratio (MEPAR) (%) and integrated SAI showed significant improvement after tDCS (p < 0.01 and p < 0.01). The mean values of the change in integrated SAI (%) were significantly correlated with the changes in UPDRS-III scores; however, the MoCA-K and BDI scores did not show differences.ConclusionsAnodal tDCS could influence the central cholinergic system, such as frontal cortical excitability and depression in PD. This mechanism could underlie the clinical benefit of tDCS in patients with PD.

Isolated Amyloid-β Pathology Is Associated with Preserved Cortical Plasticity in APOE4 Alzheimer's Disease Patients.

Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer's disease (AD) patients. In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer's Association (NIA-AA) classification and APOE genotype. 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of amyloid-β (Aβ) deposition (A) and fibrillar tau (T), in four groups: A+/T-E4 (n = 9), A+/T-E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation protocol over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination (MMSE) scores respect to the baseline. A+/T-E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T-E3 and to A+/T+ patients independently from genotype (p < 0.001). In addition, A+/T-E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (delta MMSE -0.5±2.12 versus -6.05±4.95; post-hocp = 0.004) and to A+/T+ E3 patients (-4.12±4.14; post-hoc p = 0.028). No differences were found for SAI protocol (p > 0.05). Our results suggest that APOE4 in patients with isolated Aβ pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

Neurophysiological Correlates of Motor and Cognitive Dysfunction in Prodromal and Overt Dementia with Lewy Bodies.

The neurophysiological correlates of cognitive and motor symptoms in prodromal and overt dementia with Lewy bodies (DLB) are still to be elucidated. To evaluate if cognitive and motor features of patients with prodromal and overt DLB are associated with the impairment of specific neurotransmitter circuits, evaluated in vivo with transcranial magnetic stimulation (TMS). Fifty-one patients with DLB (twenty-five prodromal; twenty-six with dementia) underwent neuropsychological and clinical evaluation, with twenty-five patients having at least one follow-up evaluation. All patients were assessed with TMS at baseline, with protocols assessing cholinergic circuits (short latency afferent inhibition, SAI), GABAergic circuits (short interval intracortical inhibition, SICI), and glutamatergic circuits (intracortical facilitation, ICF). Compared to HC, SICI, ICF, and SAI resulted significantly impaired in both prodromal and overt DLB, with the latter showing a reduced SICI and SAI also compared to prodromal DLB. There was a significant correlation between motor deficits, evaluated with the UPDRS-III, and the impairment of GABAergic (SICI) (r = 0.729, p < 0.001) and glutamatergic (ICF) (r -0.608, p < 0.001) circuits; global cognition, evaluated with the Mini-Mental State Examination, correlated with the impairment of cholinergic (SAI) circuits (r=-0.738, p < 0.001). Worsening of cognitive functions at follow-up was associated with reduced cholinergic functions at baseline (R2 = 0.53, p < 0.001). These results suggest that motor and cognitive dysfunctions in prodromal and overt DLB depend on specific and independent neurotransmitter circuits.

Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.

Background and purposeFatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS‐CoV‐2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions.MethodsSixty‐seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS‐CoV‐2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16‐item questionnaire. Fatigue, exertion, cognitive difficulties, mood and ‘well‐being’ were evaluated through self‐administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short‐interval intracortical inhibition, intracortical facilitation, long‐interval intracortical inhibition and short‐latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks.ResultsPost COVID‐19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well‐being and reduced mental well‐being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long‐interval intracortical inhibition and short‐latency afferent inhibition were also impaired, indicating altered GABAB‐ergic and cholinergic neurotransmission. Short‐interval intracortical inhibition and intracortical facilitation were not affected. Patients also showed poorer global cognition and executive functions compared to HCs and a clear impairment in sustained and executive attention.ConclusionsPatients with fatigue and cognitive difficulties following mild COVID‐19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.

Short latency afferent inhibition: comparison between threshold-tracking and conventional amplitude recording methods.

Short-latency afferent inhibition (SAI), which is conventionally measured as a reduction in motor evoked potential amplitude (A-SAI), is of clinical interest as a potential biomarker for cognitive impairment. Since threshold-tracking has some advantages for clinical studies of short-interval cortical inhibition, we have compared A-SAI with a threshold-tracking alternative method (T-SAI). In the T-SAI method, inhibition was calculated by tracking the required TMS intensity for the targeted MEP amplitude (200 uV) both for the test (TMS only) and paired (TMS and peripheral stimulation) stimuli. A-SAI and T-SAI were recorded from 31 healthy subjects using ten stimuli at each of 12 inter-stimulus intervals, once in the morning and again in the afternoon. There were no differences between morning and afternoon recordings. When A-SAI was normalized by log conversion it was closely related to T-SAI. Between subjects, variability was similar for the two techniques, but within-subject variability was significantly smaller for normalized A-SAI. Conventional amplitude measurements appear more sensitive for detecting changes within-subjects, such as in interventional studies, but threshold-tracking may be as sensitive as detecting abnormal SAI in a patient.