Synaptic plasticity in neurodegenerative diseases evaluated and modulated by in vivo neurophysiological techniques.

Several studies demonstrated in experimental models and in humans synaptic plasticity impairment in some neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and schizophrenia. Recently new neurophysiological tools, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, have been introduced in experimental and clinical settings for studying physiology of the brain and modulating cortical activity. These techniques use noninvasive transcranial electrical or magnetic stimulation to modulate neurons activity in the human brain. Cortical stimulation might enhance or inhibit the activity of cortico-subcortical networks, depending on stimulus frequency and intensity, current polarity, and other stimulation parameters such as the configuration of the induced electric field and stimulation protocols. On this basis, in the last two decades, these techniques have rapidly become valuable tools to investigate physiology of the human brain and have been applied to treat drug-resistant neurological and psychiatric diseases. Here we describe these techniques and discuss the mechanisms that may explain these effects.

Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease.

OBJECTIVES: Recent transcranial magnetic stimulation (TMS) studies demonstrate that motor cortex excitability is increased in Alzheimer's disease (AD) and that intracortical inhibitory phenomena are impaired. The aim of the present study was to determine whether hyperexcitability is due to the impairment of intracortical inhibitory circuits or to an independent abnormality of excitatory circuits. METHODS: We assessed the excitability of the motor cortex with TMS in 28 patients with AD using several TMS paradigms and compared the data of cortical excitability (evaluated by measuring resting motor threshold) with the amount of motor cortex disinhibition as evaluated using the test for motor cortex cholinergic inhibition (short latency afferent inhibition) and GABAergic inhibition (short latency intracortical inhibition). The data in AD patients were also compared with that from 12 age matched healthy individuals. RESULTS: The mean resting motor threshold was significantly lower in AD patients than in controls. The amount of short latency afferent inhibition was significantly smaller in AD patients than in normal controls. There was also a tendency for AD patients to have less pronounced short latency intracortical inhibition than controls, but this difference was not significant. There was no correlation between resting motor threshold and measures of either short latency afferent or intracortical inhibition (r = -0.19 and 0.18 respectively, NS). In 14 AD patients the electrophysiological study was repeated after a single oral dose of the cholinesterase inhibitor rivastigmine. Resting motor threshold was not significantly modified by the administration of rivastigmine. In contrast, short latency afferent inhibition from the median nerve was significantly increased by the administration of rivastigmine. CONCLUSIONS: The change in threshold did not seem to correlate with dysfunction of inhibitory intracortical cholinergic and GABAergic circuits, nor with the central cholinergic activity. We propose that the hyperexcitability of the motor cortex is caused by an abnormality of intracortical excitatory circuits.

Changes in motor cortex excitability in facioscapulohumeral muscular dystrophy.

Previous studies found that some patients with severe, early onset facioscapulohumeral muscular dystrophy (FSHD) present epilepsy and mental retardation. This suggests a functional involvement of central nervous system in severe FSHD. It is unknown whether minor functional changes of central nervous system are also present in less severe forms of FSHD. To investigate this, we examined the excitability of neuronal networks of the motor cortex with a range of transcranial magnetic stimulation paradigms in 20 FSHD patients with heterogeneous clinical severity and compared the data with that from 20 age-matched healthy individuals and from 6 age-matched patients with other muscle diseases. There was significantly less intracortical inhibition in FSHD patients (mean responses +/- SD reduced to 58.1+/-43.5% of the test size) than in controls (mean responses +/- SD reduced to 29.3+/-13.5% of the test size; P=0.025) and in patients with other muscle diseases (mean responses +/-SD, reduced to 30.6+/-11.7% of the test size; P=0.046). No significant difference was found between the control group and patients with other muscle diseases (P=0.970).

Direct demonstration of reduction of the output of the human motor cortex induced by a fatiguing muscle contraction.

A brief period of strong muscle contraction suppresses the amplitude of EMG responses evoked in relaxed muscle by transcranial magnetic stimulation (TMS) of the contralateral motor cortex. Here we investigate this phenomenon in more detail by recording the descending motor volleys evoked by TMS from electrodes in the cervical epidural space of three conscious patients implanted with chronic electrical stimulators for control of pain. We confirm that fatigue suppresses I waves evoked by TMS. In addition, D waves were suppressed in two of the patients, suggesting that axonal excitability might also be compromised by a period of intense muscle contraction.

Direct demonstration of long latency cortico-cortical inhibition in normal subjects and in a patient with vascular parkinsonism.

OBJECTIVE: The motor evoked potential to a single suprathreshold transcranial magnetic stimulus (TMS) is suppressed by a preceding stimulus given 100-200 ms before (long latency intracortical inhibition, LICI). The effect is enhanced in patients with Parkinson's disease. Although previous studies have agreed that the effect is cortical, there is disagreement over exactly which cortical mechanisms are involved. The aim of this study was to provide further evidence for cortical involvement in LICI. METHODS: Recordings of corticospinal volleys evoked by the TMS stimulation were made from electrodes inserted into the cervical epidural space of 4 conscious subjects. Three of the patients had received the electrodes for treatment of lumbo-sacral pain; the other patient had vascular parkinsonism, and had the electrode implanted to evaluate its effect on cerebral blood flow. The number and amplitude of the volleys were compared with and without a conditioning stimulus. RESULTS: In 3 pain patients, a conditioning stimulus suppressed the later components of the corticospinal volley (I2 and later waves) when the interval between stimuli was 100-150 ms; at 50 ms the responses were enhanced. Early components of the volley were not affected. Inhibition was much more pronounced and involved all descending volleys except the D wave in the patient with vascular parkinsonism. CONCLUSIONS: LICI, which is conventionally described in EMG recordings, is also evident in recordings of descending corticospinal volleys and appears enhanced in a patient with vascular parkinsonism.

Intermuscular coherence in Parkinson's disease: relationship to bradykinesia.

We hypothesised that bradykinesia may be partly due to the failure of the corticomuscular system to engage in high frequency oscillatory activity in Parkinson's disease (PD). In healthy subjects such oscillations are evident in coherence between active muscles at 15--30 Hz. We therefore investigated the effects of therapeutic stimulation of the basal ganglia on this coherence and related it to changes in bradykinesia in the contralateral arm. Increases in coherence at 15--30 Hz and improvements in bradykinesia upon stimulation were correlated (r = 0.564, p < 0.001). This suggests that the basal ganglia modulate oscillatory activity in the corticomuscular system and that impairment of the motor system's ability to engage in synchronised oscillations at high frequency may contribute to bradykinesia in PD.

Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex.

OBJECTIVES: The present study explored the effects of lorazepam, a benzodiazepine with agonist action at the GABA(A) receptor, on human motor cortex excitability as tested using transcranial magnetic stimulation. METHODS: We recorded directly the descending volley evoked by single and paired transcranial magnetic stimulation from the spinal cord of a conscious subject with a cervical epidural electrode before and after a single oral dose of lorazepam. We evaluated the effects of lorazepam on the descending volleys evoked by a single magnetic stimulation and paired cortical stimulation using the intracortical inhibition paradigm (subthreshold conditioning stimulus) and the short latency intracortical facilitation paradigm (suprathreshold conditioning stimulus). RESULTS: Using a single magnetic stimulus lorazepam decreased the amplitude of the later I waves in the descending volley; this was accompanied by a decrease in the amplitude of the evoked EMG response. Using the intracortical inhibition paradigm lorazepam increased the amount of corticocortical inhibition, particularly at 4 and 5 ms interstimulus intervals. There was no effect on the amount of facilitation observed in the short latency intracortical facilitation paradigm. CONCLUSIONS: The present findings provide direct evidence that lorazepam increases the excitability of inhibitory circuits in the human motor cortex.

Intracortical origin of the short latency facilitation produced by pairs of threshold magnetic stimuli applied to human motor cortex.

Under certain conditions, EMG responses evoked by pairs of transcranial magnetic stimuli over the motor cortex are larger than the sum of the responses to each stimulus given alone. This occurs with interstimulus intervals of around 1.3, 2.5 and 4.3 ms and could be due to interaction between the responses to each stimulus at either the cortex or spinal cord. We recorded the descending volleys set up by such pairs of stimuli from the cervical epidural space of five patients implanted with chronic stimulators for pain control. Interstimulus intervals of 1, 1.2, 1.4 and 2 ms were used to investigate the first peak of facilitation. Enhanced EMG responses occurred after pairs of stimuli at 1, 1.2 and 1.4 ms, and these were accompanied by larger and more numerous descending volleys than expected from the sum of each stimulus alone. We conclude that facilitatory interaction between the stimuli can occur within the cerebral cortex. This may involve elements that produce repetitive I-wave activity in response to a single stimulus.

Brain-stem somatosensory dysfunction in a case of long-standing left hemispherectomy with removal of the left thalamus: a nasopharyngeal and scalp SEP study.

We have studied median nerve somatosensory evoked potentials (SEPs) in a patient who had undergone early surgical removal of the left cerebral hemisphere and left thalamus. Stimulation of the right side evoked normal latency P9, P11 and P13 potentials at scalp as well as at nasopharyngeal (NP) leads, while P14 and N18 potentials were absent. These SEP abnormalities, that have been described previously in cervico-medullary lesions and in comatose patients with upper brain-stem involvement, suggest that in our patient the removal of the left thalamus has caused retrograde degeneration of the cuneate-thalamic projections. Moreover, this study confirms that P13 and P14 potentials have different generators.

Click-evoked vestibulocollic reflexes in torticollis.

A total of 26 patients with torticollis were studied using a recently developed technique for recording vestibulocollic reflexes from the sternocleidomastoid muscles in addition to conventional caloric tests of vestibular function. Previous reports of abnormalities of vestibulo-ocular reflexes in these patients were confirmed with just fewer than half having significant canal pareses or directional preponderances (nine of 20 tested). In addition, there was a high incidence of abnormal click-evoked vestibulocollic reflexes (17 of 26 tested), which were not simply the result of prior treatment with botulinum toxin, nor due to unequal levels of muscle activation. In patients never previously treated with botulinum toxin (14 patients), the effect almost always consisted of suppressed responses in the sternocleidomastoid muscle ipsilateral to the direction of head turning. Because responses were not abnormal in all patients tested, and more commonly so in those with a history of torticollis of > or = 5 years (eight of nine patients) than in de novo patients, we suggest that the changes are more likely to be compensatory than causal.

Short-latency trigemino-cervical reflexes in man.

We describe a reflex evoked in neck muscles by stimulation of afferent fibres in the trigeminal nerve. The clearest responses were seen in averaged, unrectified, monopolar surface electromyographic (EMG) recordings from active sternocleidomastoid muscles after stimulation of the infraorbital nerve. They consisted of a bilateral positive/negative (p19, n31) wave with a mean onset latency of 12.9 ms which corresponded to a period of inhibition in the underlying motor unit activity. Responses also could be seen in splenius and trapezius, but not in arm muscles. Stimuli to other branches of the trigeminal nerve (supraorbital or mental) did not produce such clear effects. The threshold for the reflex was relatively low (2-4 times perceptual threshold) and its size scaled with the level of background EMG in an approximately linear fashion. Responses to infraorbital stimulation did not interact with other short-latency inhibitory responses in the sternocleidomastoid muscle evoked by loud acoustic clicks or stimulation of the median nerve at the wrist. We suggest that the infraorbital response is part of a head withdrawal reflex involving an oligosynaptic trigemino-cervical system similar to that described in the cat.