Alessandro Di Rocco

Repetitive Transcranial Magnetic Stimulation Enhances BDNF–TrkB Signaling in Both Brain and Lymphocyte

Repetitive transcranial magnetic stimulation (rTMS) induces neuronal long-term potentiation or depression. Although brain-derived neurotrophic factor (BDNF) and its cognate tyrosine receptor kinase B (TrkB) contribute to the effects of rTMS, their precise role and underlying mechanism remain poorly understood. Here we show that daily 5 Hz rTMS for 5 d improves BDNF–TrkB signaling in rats by increasing the affinity of BDNF for TrkB, which results in higher tyrosine-phosphorylated TrkB, increased recruitment of PLC-γ1 and shc/N-shc to TrkB, and heightened downstream ERK2 and PI-3K activities in prefrontal cortex and in lymphocytes. The elevated BDNF–TrkB signaling is accompanied by an increased association between the activated TrkB and NMDA receptor (NMDAR). In normal human subjects, 5 d rTMS to motor cortex decreased resting motor threshold, which correlates with heightened BDNF–TrkB signaling and intensified TrkB–NMDAR association in lymphocytes. These findings suggest that rTMS to cortex facilitates BDNF–TrkB–NMDAR functioning in both cortex and lymphocytes.

Apathy, but Not Depression, Reflects Inefficient Cognitive Strategies in Parkinson's Disease

Background The relationship between apathy, depression and cognitive impairment in Parkinsons disease (PD) is still controversial. The objective of this study is to investigate whether apathy and depression are associated with inefficient cognitive strategies in PD. Methods In this prospective clinical cohort study conducted in a university-based clinical and research movement disorders center we studied 48 PD patients. Based on clinical evaluation, they were classified in two groups: PD with apathy (PD-A group, n = 23) and PD without apathy (PD-NA group, n = 25). Patients received clinical and neuropsychological evaluations. The clinical evaluation included: Apathy Evaluation Scale-patient version, Hamilton Depression Rating Scale-17 items, the Unified Parkinsons Disease Rating Scale and the Hoehn and Yahr staging system; the neuropsychological evaluation explored speed information processing, attention, working memory, executive function, learning abilities and memory, which included several measures of recall (immediate free, short delay free, long delay free and cued, and total recall). Findings PD-A and PD-NA groups did not differ in age, disease duration, treatment, and motor condition, but differed in recall (p<0.001) and executive tasks (p<0.001). Immediate free recall had the highest predictive value for apathy (F =  10.94; p = 0.002). Depression and apathy had a weak correlation (Pearson index  = 0.3; p<0.07), with three items of the depression scale correlating with apathy (Pearson index between .3 and.4; p<0.04). The depressed and non-depressed PD patients within the non-apathetic group did not differ. Conclusion Apathy, but not depression, is associated with deficit in implementing efficient cognitive strategies. As the implementation of efficient strategies relies on the fronto-striatal circuit, we conclude that apathy, unlike depression, is an early expression of executive impairment in PD.

Methionine in the treatment of nitrous-oxide-induced neuropathy and myeloneuropathy

SummaryTwo cases of severe myeloneuropathy and macrocytic anemia associated with a low serum level of vitamin B12 after prolonged exposure to nitrous oxide are reported. In both cases, the neurological manifestations worsened initially despite B12 supplementation, al though in one case the use of methionine seemed to arrest the progression of the disease and accelerate recovery. This offers further support for the biochemical hypothesis of methionine synthetase inhibition by nitrous oxide and reproduces in man previously reported animal studies with methionine. Methionine may be an important first-line therapy in the initial treatment of neuropathy and myeloneuropathy induced by nitrous oxide, and has a hypothetical role in the treatment of subacute combined degeneration of the cord.

Cortical and brainstem LTP-like plasticity in Huntington's disease

Recent studies have reported abnormalities in short-term plasticity in patients with Huntingtons disease (HD). However, is not known whether long-term potentiation (LTP)-like plasticity is also affected in these patients. We tested cortical and brainstem LTP-like plasticity in eight symptomatic HD patients and in 10 healthy age-matched controls. To probe motor cortex LTP-like plasticity we used paired associative stimulation (PAS), a technique that combines repetitive electric stimulation of the median nerve with subsequent transcranial magnetic stimulation (TMS) of the contralateral motor cortex at 25 ms. To investigate brainstem plasticity, we induced LTP-like phenomena in the trigeminal wide dynamic range neurons (WDR) of the blink reflex circuit by pairing an high-frequency train of electrical stimuli (HFS) over the right supraorbital nerve (SO) coincident with the R2 response elicited by a preceding SO stimulus. Our results demonstrate impairment of both cortical and brainstem LTP-like plasticity in symptomatic HD patients which is similar to LTP deficits previously reported in HD animal models. These findings might well represent the neurophysiological correlates of memory deficits often present in HD.

Modulation of Gamma and Theta Spectral Amplitude and Phase Synchronization Is Associated with the Development of Visuo-Motor Learning

The formation of new motor memories, which is fundamental for efficient performance during adaptation to a visuo-motor rotation, occurs when accurate planning is achieved mostly with feedforward mechanisms. The dynamics of brain activity underlying the switch from feedback to feedforward control is still matter of debate. Based on the results of studies in declarative learning, it is likely that phase synchronization of low and high frequencies as well as their temporal modulation in power amplitude underlie the formation of new motor memories during visuo-motor adaptation. High-density EEG (256 electrodes) was recorded in 17 normal human subjects during adaptation to a visuo-motor rotation of 60° in four incremental steps of 15°. We found that initial learning is associated with enhancement of gamma power in a right parietal region during movement execution as well as gamma/theta phase coherence during movement planning. Late stages of learning are instead accompanied by an increase of theta power over that same right parietal region during movement planning, which is correlated with the degree of learning and retention. Altogether, these results suggest that the formation of new motor memories and, thus, the switch from feedback to feedforward control is associated with the modulation of gamma and theta spectral activities, with respect to their amplitude and phase, during movement planning and execution. Specifically, we propose that gamma/theta phase coupling plays a pivotal role in the integration of a new representation into motor memories.

Treatment of Advanced Parkinson's Disease

Patients at late stage Parkinsons disease (PD) develop several motor and nonmotor complications, which dramatically impair their quality of life. These complications include motor fluctuations, dyskinesia, unpredictable or absent response to medications, falls, dysautonomia, dementia, hallucinations, sleep disorders, depression, and psychosis. The therapeutic management should be driven by the attempt to create a balance between benefit and side effects of the pharmacological treatments available. Supportive care, including physical and rehabilitative interventions, speech therapy, occupational therapy, and nursing care, has a key role in the late stage of disease. In this review we discuss the several complications experienced by advance PD patients and their management. The importance of an integrative approach, including both pharmacological and supportive interventions, is emphasized.

Multifocal repetitive TMS for motor and mood symptoms of Parkinson disease: A randomized trial

Objective: To assess whether multifocal, high-frequency repetitive transcranial magnetic stimulation (rTMS) of motor and prefrontal cortex benefits motor and mood symptoms in patients with Parkinson disease (PD). Methods: Patients with PD and depression were enrolled in this multicenter, double-blind, sham-controlled, parallel-group study of real or realistic (electric) sham rTMS. Patients were randomized to 1 of 4 groups: bilateral M1 ( + sham dorsolateral prefrontal cortex [DLPFC]), DLPFC ( + sham M1), M1 + DLPFC, or double sham. The TMS course consisted of 10 daily sessions of 2,000 stimuli for the left DLPFC and 1,000 stimuli for each M1 (50 × 4-second trains of 40 stimuli at 10 Hz). Patients were evaluated at baseline, at 1 week, and at 1, 3, and 6 months after treatment. Primary endpoints were changes in motor function assessed with the Unified Parkinsons Disease Rating Scale-III and in mood with the Hamilton Depression Rating Scale at 1 month. Results: Of the 160 patients planned for recruitment, 85 were screened, 61 were randomized, and 50 completed all study visits. Real M1 rTMS resulted in greater improvement in motor function than sham at the primary endpoint (p < 0.05). There was no improvement in mood in the DLPFC group compared to the double-sham group, as well as no benefit to combining M1 and DLPFC stimulation for either motor or mood symptoms. Conclusions: In patients with PD with depression, M1 rTMS is an effective treatment of motor symptoms, while mood benefit after 2 weeks of DLPFC rTMS is not better than sham. Targeting both M1 and DLPFC in each rTMS session showed no evidence of synergistic effects. ClinicalTrials.gov identifier: NCT01080794. Classification of evidence: This study provides Class I evidence that in patients with PD with depression, M1 rTMS leads to improvement in motor function while DLPFC rTMS does not lead to improvement in depression compared to sham rTMS.

Axonal damage is a late component of vacuolar myelopathy.

Abstract—The role of axonopathy in myelin disorders recently has been examined. To investigate axonal pathologic changes in vacuolar myelopathy (VM), semiquantitative immunohistochemical stains for inflammation, axonal damage, and gliosis were performed on spinal cord sections from patients with AIDS with and without VM and from HIV-negative controls. Significant axonal damage was present in only moderate to severe VM, despite inflammation at all stages. The authors conclude that axonal damage is not present in early disease; it is present in moderate to severe vacuolar myelopathy and may contribute to clinical deficits in late stages of this disorder.

Protracted exercise without overt neuromuscular fatigue influences cortical excitability.

ABSTRACT The authors’ aim was to determine the cortical mechanisms that underlie the transition from effective performance to its disruption. They thus used transcranial magnetic stimulation (TMS) to study changes of corticospinal excitability after a motor exercise that did not produce overt or perceived neuromuscular fatigue. Forty-four subjects performed either 5 or 10 min of repetitive finger movements paced by tones at 2 Hz, a frequency below the spontaneous movement rate. Changes of corticospinal excitability were assessed with TMS at rest and during motor response preparation (premovement facilitation paradigm). Over time, variability of movement rate increased, while the average movement rate shifted toward self-paced rhythms, without significant changes in other kinematic parameters. Amplitudes of motor evoked potentials at rest decreased depending on task duration and TMS intensity. Moreover, 5-min exercise induced fully compensatory increases in premovement facilitation, while 10-min exercise produced partially compensatory increases with loss of temporal modulation. Our findings suggest that protracted exercise induces significant decrements in corticospinal excitability with initial impairment of the phasic motor neurons that are recruited at higher stimulus intensities. Changes in premovement facilitation likely represent compensation of premotor areas for decreased efficiency of the primary motor cortex induced by exercise.

Increased reaction time predicts visual learning deficits in Parkinson's disease†

To determine whether the process involved in movement preparation of patients in the early stages of Parkinsons disease (PD) shares attentional resources with visual learning, we tested 23 patients with PD and 13 healthy controls with two different tasks. The first was a motor task where subjects were required to move as soon as possible to randomly presented targets by minimizing reaction time. The second was a visual learning task where targets were presented in a preset order and subjects were asked to learn the sequence order by attending to the display without moving. Patients with PD showed higher reaction and movement times, while visual learning was reduced compared with controls. For patients with PD, reaction times, but not movement times, displayed an inverse significant correlation with the scores of visual learning. We conclude that visual declarative learning and movement preparation might share similar attentional and working memory resources.