Abnormal motor cortical plasticity as a useful neurophysiological biomarker for Alzheimer's disease pathology.

OBJECTIVE: Amyloid-beta (Aß) and tau accumulations impair long-term potentiation (LTP) induction in animal hippocampi. We investigated relationships between motor-cortical plasticity and biomarkers for Alzheimer's disease (AD) diagnosis in subjects with cognitive decline. METHODS: Twenty-six consecutive subjects who complained of memory problems participated in this study. We applied transcranial quadripuse stimulation with an interstimulus interval of 5 ms (QPS5) to induce LTP-like plasticity. Motor-evoked potentials were recorded from the right first-dorsal interosseous muscle before and after QPS5. Cognitive functions, Aß42 and tau levels in the cerebrospinal fluid (CSF) were measured. Amyloid positron-emission tomography (PET) with11C-Pittsburg compound-B was also conducted. We studied correlations of QPS5-induced plasticity with cognitive functions or AD-related biomarkers. RESULTS: QPS5-induced LTP-like plasticity positively correlated with cognitive scores. The degree of LTP-like plasticity negatively correlated with levels of CSF-tau, and the amount of amyloid-PET accumulation at the precuneus, and correlated with the CSF-Aß42 level positively. In the amyloid-PET positive subjects, non-responder rate of QPS5 was higher than the CSF-tau positive rate. CONCLUSIONS: Findings suggest that QPS5-induced LTP-like plasticity is a functional biomarker of AD. QPS5 could detect abnormality at earlier stages than CSF-tau in the amyloid-PET positive subjects. SIGNIFICANCE: Assessing motor-cortical plasticity could be a useful neurophysiological biomarker for AD pathology.

Effectiveness of transcranial direct current stimulation (tDCS) as adjunctive treatment for chronic headache in adults with clinically stable systemic lupus erythematosus (SHADE): a randomised double-blind multiarm sham controlled clinical trial.

BACKGROUND: Chronic headache is a 'silent' neuropsychiatric systemic lupus erythematosus symptom with heterogeneous prevalence, potentially reaching 54.4%. It may reduce quality of life by increasing the likelihood of depression and sleep disturbance. While pharmacotherapy remains the first-line treatment, the current management is still challenging and needs other non-invasive modalities. An effective, tolerable and disease-specific treatment modality including transcranial direct current stimulation (tDCS) is considered to reduce the frequency of chronic headaches, including in SLE. Until recently, there was no standard protocol for tDCS in treating headaches. METHODS AND ANALYSIS: SHADE is a single-centre randomised double-blind multiarm sham-controlled trial for adults with clinically stable SLE, chronic headaches and without history of traumatic brain injury, brain infection, stroke or brain tumour. Random allocation is conducted to 88 subjects into 3 treatment groups (administration at primary motor, primary sensory and dorsolateral prefrontal cortex) and control group in 1:1:1:1 ratio. The primary endpoint is reduced number of headache days after adjunctive tDCS. The secondary endpoints are reduced headache intensity, increased quality of life, increased sleep quality, decreased depression and reduced analgesics use. The outcome is measured monthly until 3-month postintervention using headache diary, 36-Item Short Form Survey, Chronic Headache Quality of Life Questionnaire, Pittsburgh Sleep Quality Index and Mini International Neuropsychiatry Interview version 10 (MINI ICD 10). Intention-to-treat analysis will be performed to determine the best tDCS electrode placement. ETHICS AND DISSEMINATION: Ethical approval had been obtained from the local Institutional Review Board of Faculty of Medicine Universitas Indonesia. Results will be published through scientific relevant peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05613582.

Enhancement of LTD-like plasticity by associative pairing of quadripulse magnetic stimulation with peripheral nerve stimulation.

OBJECTIVE: Quadripulse magnetic stimulation (QPS) is useful for changing corticospinal excitability, but the long-term depression (LTD)-like effect considerably has low responder rate. To solve this problem, we modified inhibitory QPS (QPSLTD) by pairing it with the application of an electrical stimulus (ES) to peripheral nerves (paired-associative QPS [PA-QPSLTD]), and investigated the effects of PA-QPSLTD on motor-evoked potentials (MEPs). METHODS: The peripheral-nerve ES was applied at two timings with a synchrony to transcranial magnetic stimulation (TMS) over the primary motor cortex (M1). The intrapair interval between ES and TMS was the N20-peak latency plus 2 ms for PALTP-QPSLTD, and N20-peak latency minus 5 ms for PALTD-QPSLTD. MEPs elicited by TMS over the left M1 were recorded from the right abductor pollicis brevis muscle before and after the interventions. The responder rates of PALTD-QPSLTD and QPSLTD was also studied. RESULTS: The PALTD-QPSLTD induced larger LTD-like effect than QPSLTD, and the PALTP-QPSLTD induced smaller aftereffect than QPSLTD. The responder rates were significantly higher for PALTD-QPSLTD than for QPSLTD. CONCLUSIONS: The new protocol, PALTD-QPSLTD, induces powerful and consistent LTD-like aftereffects in the corticospinal tract neurons. SIGNIFICANCE: PALTD-QPSLTD is suitable for use in physiological evaluations and therapeutic approaches in various neurological disorders.

Direct comparison of efficacy of the motor cortical plasticity induction and the interindividual variability between TBS and QPS.

BACKGROUND: Theta burst stimulation (TBS) and quadripulse stimulation (QPS) are known to induce synaptic plasticity in humans. There have been no head-to-head comparisons of the efficacy and variability between TBS and QPS. OBJECTIVE: To compare the efficacy and interindividual variability between the original TBS and QPS protocols. We hypothesized that QPS would be more effective and less variable than TBS. METHODS: Forty-six healthy subjects participated in this study. Thirty subjects participated in the main comparison experiment, and the other sixteen subjects participated in the experiment to obtain natural variation in motor-evoked potentials. The facilitatory effects were compared between intermittent TBS (iTBS) and QPS5, and the inhibitory effects were compared between continuous TBS (cTBS) and QPS50. The motor-evoked potential amplitudes elicited by transcranial magnetic stimulation over the primary motor cortex were measured before the intervention and every 5 min after the intervention for 1 h. To investigate the interindividual variability, the responder/nonresponder/opposite-responder rates were also analyzed. RESULTS: The facilitatory effects of QPS5 were greater than those of iTBS, and the inhibitory effects of QPS50 were much stronger than those of cTBS. The responder rate of QPS was significantly higher than that of TBS. QPS had a smaller number of opposite responders than TBS. CONCLUSION: QPS is more effective and stable for synaptic plasticity induction than TBS.

A patient with McLeod syndrome showing involvement of the central sensorimotor tracts for the legs.

BACKGROUND: McLeod syndrome is a rare X-linked recessive acanthocytosis associated with neurological manifestations including progressive chorea, cognitive impairment, psychiatric disturbances, seizures, and sensorimotor axonal polyneuropathy. However, no studies have investigated the functioning of central sensorimotor tracts in patients with McLeod syndrome. CASE PRESENTATION: A 66-year-old man had experienced slowly progressive chorea and gait disturbance due to lower limb muscle weakness since his early fifties. Blood examinations showed erythrocyte acanthocytosis and the reduction of Kell antigens in red blood cells. Brain magnetic resonance imaging showed atrophy of the bilateral caudate nuclei and putamen. The diagnosis of McLeod syndrome was confirmed by the presence of a mutation of the XK gene on the X chromosome. Somatosensory-evoked potential and transcranial magnetic stimulation studies demonstrated that the central sensory and motor conduction times were abnormally prolonged for the lower extremity but normal for the upper extremity. CONCLUSIONS: This is the first report of the involvement of the central sensorimotor tracts for the legs in a patient with McLeod syndrome. The clinical neurophysiological technique revealed the central sensorimotor tracts involvements clinically masked by neuropathy.

The Motor Network Reduces Multisensory Illusory Perception.

Observing mouth movements has strikingly effects on the perception of speech. Any mismatch between sound and mouth movements will result in listeners perceiving illusory consonants (McGurk effect), whereas matching mouth movements assist with the correct recognition of speech sounds. Recent neuroimaging studies have yielded evidence that the motor areas are involved in speech processing, yet their contributions to multisensory illusion remain unclear. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) in an event-related design, we aimed to identify the functional roles of the motor network in the occurrence of multisensory illusion in female and male brains. fMRI showed bilateral activation of the inferior frontal gyrus (IFG) in audiovisually incongruent trials. Activity in the left IFG was negatively correlated with occurrence of the McGurk effect. The effective connectivity between the left IFG and the bilateral precentral gyri was stronger in incongruent than in congruent trials. The McGurk effect was reduced in incongruent trials by applying single-pulse TMS to motor cortex (M1) lip areas, indicating that TMS facilitates the left IFG-precentral motor network to reduce the McGurk effect. TMS of the M1 lip areas was effective in reducing the McGurk effect within the specific temporal range from 100 ms before to 200 ms after the auditory onset, and TMS of the M1 foot area did not influence the McGurk effect, suggesting topographical specificity. These results provide direct evidence that the motor network makes specific temporal and topographical contributions to the processing of multisensory integration of speech to avoid illusion.SIGNIFICANCE STATEMENT The human motor network, including the inferior frontal gyrus and primary motor cortex lip area, appears to be involved in speech perception, but the functional contribution to the McGurk effect is unknown. Functional magnetic resonance imaging revealed that activity in these areas of the motor network increased when the audiovisual stimuli were incongruent, and that the increased activity was negatively correlated with perception of the McGurk effect. Furthermore, applying transcranial magnetic stimulation to the motor areas reduced the McGurk effect. These two observations provide evidence that the motor network contributes to the avoidance of multisensory illusory perception.