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. 2011 Feb 7;589(Pt 7):1619–1626. doi: 10.1113/jphysiol.2010.201111

Acute and chronic effects of hypercalcaemia on cortical excitability as studied by 5 Hz repetitive transcranial magnetic stimulation

Elisa Iacovelli 1, Francesca Gilio 2, Maria Lucia Mascia 3, Alfredo Scillitani 4, Elisabetta Romagnoli 3, Floriana Pichiorri 1, Sergio Fucile 5,6, Salvatore Minisola 3, Maurizio Inghilleri 1
PMCID: PMC3099019  PMID: 21300754

Non-technical summary

Calcium ions play crucial roles in many forms of synaptic plasticity at central nervous system level. We studied the effects of chronic and acute hypercalcaemia on synaptic plasticity in patients with primary hyperparathyroidism and healthy controls by applying over the primary motor cortex a non-invasive neurophysiological technique named repetitive transcranial magnetic stimulation (rTMS). Our results showed that conditions of hypercalcaemia decreased synaptic plasticity as tested by rTMS. Our results may help to understand the mechanisms underlying neuronal dysfunctions during hypercalcaemia and to evaluate asymptomatic patients.

Abstract

Abstract

We designed the present study to disclose changes in cortical excitability in humans with hypercalcaemia, by delivering repetitive transcranial magnetic stimulation (rTMS) over the primary motor area (M1). In 22 patients with chronic hypercalcaemia related to primary hyperparathyroidism and 22 age-matched healthy subjects 5 Hz-rTMS was delivered at rest and during a sustained voluntary contraction of the target muscle. Changes in the resting motor threshold (RMT), motor evoked potential (MEP) amplitudes and cortical silent period (CSP) duration were measured and compared in patients and healthy controls. Two of the 22 patients were re-tested after parathyroidectomy when serum calcium had normalized. In a subgroup of healthy subjects, changes in the rTMS parameters were tested before and after acute hypercalcaemia. No significant difference between healthy normocalcaemic subjects and chronic hypercalcaemic patients was found in the RMT values and MEP amplitude and CSP duration evoked by the first stimulus of the trains. During the course of 5 Hz-rTMS trains, MEP size increased significantly less in patients with chronic hypercalcaemia than in healthy subjects, whereas the CSP duration lengthened to a similar extent in both groups. In the two patients studied after parathyroidectomy, rTMS elicited a normal MEP amplitude facilitation. Our findings indicate that acute hypercalcaemia significantly decreased the MEP amplitude facilitation. Given that 5 Hz-rTMS modulates cortical excitability through mechanisms resembling short-term synaptic enhancement, the reduction of MEP amplitude facilitation by hypercalcaemia may be related to Ca2+-dependent changes in synaptic plasticity.

Introduction

Primary hyperparathyroidism manifests biochemically with hypercalcaemia and elevated or unsuppressed levels of parathyroid hormone and is caused by excessive, incompletely regulated secretion of parathyroid hormone from one or more of the four parathyroid glands. The incidence has decreased over the years (Marx, 2000) and the most common clinical presentation has changed so that most patients are discovered incidentally, are asymptomatic or report only neurological non-specific symptoms (Silverberg et al. 2009). Hypercalcaemia is associated with changes in the Ca2+ concentration of the cerebrospinal fluid (Murphy et al. 1986; Tai et al. 1986), which in turns can produce varying degrees of generalized encephalopathy, ranging from mild attentional impairment to coma (Castilla-Guerra et al. 2006).

Ca2+ ions play crucial signalling roles in many forms of activity-dependent synaptic plasticity. Measurements of presynaptic intracellular free Ca2+ concentration ([Ca2+]i) and manipulation of exogenous Ca2+ buffers have disclosed roles for residual [Ca2+]i after conditioning stimulation in all stages of short-term synaptic enhancement (Malenka & Bear, 2004). This kind of plasticity involves several overlapping processes (synaptic potentiation, augmentation, post-tetanic potentiation), all requiring Ca2+ mobilization, presynaptically to increase of the transmitter release probability, or postsynaptically through the activation of N-methyl d-aspartate (NMDA) receptors (Sastry et al. 1986; Castro-Alamancos & Connors, 1996; Inghilleri et al. 2004). Despite this large amount of information on the role of [Ca2+]i in neuronal processing less is known about the direct effects of extracellular Ca2+ concentration ([Ca2+]e) on neuronal function and synaptic plasticity. A clear modulatory role of elevated [Ca2+]e on the firing rates of rat thalamic neurons has been demonstrated, suggesting that hypercalcaemia may induce the clinically observed sleepiness and lethargy (with low-frequency EEG activity) by affecting the thalamic relay and pacemaker properties (Formenti et al. 2001). These effects are due to the multiple actions of high [Ca2+]e on voltage-activated Ca2+ channels and on steady cationic currents (Formenti et al. 2001), suggesting that similar actions may be exerted also on cortical neurons of hypercalcaemic patients.

In humans, repetitive transcranial magnetic stimulation (rTMS) allows the study of the brain mechanisms underlying short-term synaptic enhancement (Castro-Alamancos & Connors, 1996). rTMS at 5 Hz delivered in short trains at suprathreshold intensity over the primary motor cortex (M1) in healthy subjects causes an increase of the motor evoked potential (MEP) amplitude that outlasts the end of trains (Pascual-Leone et al. 1994; Berardelli et al. 1998; Gilio et al. 2007). Research conducted in our laboratory using rTMS to test changes in cortical excitability induced by antiepileptic drugs mainly acting on ionotropic glutamate receptors suggests that rTMS acts on cortical excitability through mechanisms involving glutamatergic neurotransmission, resembling short-term synaptic plasticity (Gilio et al. 2002; Inghilleri et al. 2004, 2005). When rTMS is delivered during a voluntary target muscle contraction, the MEP is followed by an electromyographic (EMG) silence termed the cortical silent period (CSP) that mainly depends on the activation of cortical inhibitory interneurons (Inghilleri et al. 1993). rTMS delivered at 5 Hz frequency facilitates cortical inhibitory interneuronal activity causing inhibitory postsynaptic potentials to summate thus prolonging the CSP (Berardelli et al. 1999).

Evidence on the possible role of hypercalcaemia in short-term synaptic plasticity, is still lacking. We designed this study to investigate whether 5 Hz-rTMS discloses hypercalcaemia-induced effects on the resting motor threshold (RMT), MEP facilitation and CSP lengthening in patients with primary hyperparathyroidism and healthy subjects. Two patients with parathyroid adenoma were also re-tested 6 months after surgical treatment. In a subgroup of six healthy subjects we tested the effects of acute hypercalcaemia and determined the possible correlation between MEP amplitude changes and serum ionized Ca2+ ([Ca2+]s) concentrations.

Methods

We studied 22 patients with biochemically verified primary hyperparathyroidism (4 men and 18 women; mean age ± SD 64.9 ± 10.1 years; serum ionized calcium 1.44 ± 0.17 mmol l−1, normal range 1.17–1.33 mmol l−1; serum parathyroid hormone 81.1 ± 0.17 pg ml−1, normal range 10.6–54 pg ml−1) and 22 neurologically healthy age-matched subjects (10 women, 12 men; 64.1 ± 3.6 years). Patients were consecutively enrolled from the Osteoporosis and Metabolic Bone Disease Center ‘Sapienza’ University, Rome. A detailed medical history was obtained from each subjects. Each subject underwent physical and neurological examination, standard laboratory tests, serum vitamin B12, folate and thyroid hormone assays, electrocardiogram and magnetic resonance imaging brain scans. Control subjects and patients with major behavioural disorders, cognitive impairment (Mini Mental State Evaluation scores lower than 26/30) and with abnormal findings at neurological examination were excluded. All the subjects were able to understand the task and keep the hand muscle relaxed when required. None of the subjects was receiving medications and none of them had been treated with drugs acting on the central nervous system in the 2 weeks before the experimental session. All subjects were right-handed. Subjects were seated in a comfortable armchair fully relaxed.

Ethical approval

All participants gave their written informed consent to the study. The study was conducted in accordance with the Declaration of Helsinki. All procedures were approved by the Ethical Committee of the Department of Neurological Sciences, ‘Sapienza’ University, Rome.

Stimulation techniques

Single pulse TMS and rTMS were delivered through a high-frequency biphasic magnetic stimulator (Magstim Rapid, The Magstim Co. Ltd, Whitland, UK) connected to a figure-of-eight coil placed over M1 in the left hemisphere tangentially to the scalp with the handle pointing back and away from the midline at 45 deg. Magnetic pulses were delivered over the optimal position for evoking a MEP in the contralateral first dorsal interosseous (FDI) muscle. The RMT was calculated as the lowest intensity able to evoke a MEP with an amplitude of more than 50 μV in at least five out of 10 consecutive trials in the FDI muscle.

Experimental procedure

Effects of chronic hypercalcaemia

All healthy subjects and patients underwent rTMS delivered in trains of 10 stimuli at 5 Hz frequency with an intensity of 120% RMT (Berardelli et al. 1998). All subjects were studied at rest and during a sustained voluntary contraction of the FDI muscle (30% of the maximum electromyography, EMG, activity) on the same day with an interval of about 10 min. The order of the two conditions was randomized between subjects. In the active condition, subjects were asked to maintain an isometric contraction of the FDI muscle during rTMS trains. In order to avoid muscle fatigue they were asked to start muscle contraction about 4 s before rTMS trains, to stop muscle contraction about 4 s after the end of rTMS trains and to rest between trials. Under both experimental conditions (rest and active contraction), muscle activity was monitored through an audio feedback from loudspeakers. In each condition six trains were delivered with an inter-train interval of about 1 min. During rTMS patients were asked to remain fully relaxed and to ensure similar attention levels keeping their eyes closed.

When designing this study we took special care to ensure that we obtained reliable, reproducible rTMS data specifically reflecting changes in M1 cortical excitability uninfluenced by technical problems. To exclude an involuntary background contraction we carefully checked the EMG and excluded trials with background EMG activity. In each subject in order to avoid the variability of the amplitude of the MEP evoked by the first stimulus in the train between trials we carefully checked the optimal stimulation hot-spot. Finally, to avoid attentional or environmental distraction during rTMS we asked participants to remain fully relaxed and keep the eyes closed. A recent study in our laboratory (Conte et al. 2007) showed when subjects had to focus their attention on the stimulated hand, the MEP facilitation increased, suggesting that attentional processes influence the MEP facilitation elicited by 5 Hz-rTMS.

Study after parathyroidectomy

Two patients (patient 1, 69-year-old woman and patient 2, 60-year-old woman) were re-tested 6 months after undergoing parathyroidectomy when serum ionized calcium values remained in the normal range (1.21 mmol l−1 in patient 1 and 1.20 mmol l−1 in patient 2) without pharmacological treatment.

Effects of acute hypercalcaemia in healthy subjects

To study the effects of acute hypercalcaemia on cortical excitability and determine a possible correlation between [Ca2+]s levels with MEP amplitude changes we tested a subgroup of six healthy women (mean age ± SD 56 ± 3.5 years) not taking medications who agreed to receive intravenous (i.v.) calcium infusion as a part of their initial treatment for osteoporosis. [Ca2+]s concentrations were measured and 5 Hz-rTMS trains (10 stimuli train, 120% RMT) were delivered twice, at baseline (T0) and after i.v. calcium gluconate infusion (7 mg (kg body weight)−1, diluted in 500 ml 0.9% saline over 2 h) ended (T1). The time course of the cortical excitability changes after acute hypercalcaemia was not studied. During calcium infusion [Ca2+]s increased from a mean ± SD of 1.23 ± 0.01 mmol l−1 to 1.55 ± 0.04 mmol l−1.

Recording techniques and measurements

EMG activity was recorded through surface electrodes placed over the right FDI muscles, filtered with a Digitimer D360 device (Digitimer Ltd, Welwyn Garden City, UK) (bandwidth 20 Hz to 1 kHz) and analysed off-line with a personal computer through a 1401 plus A/D laboratory interface (Cambridge Electronic Design, Cambridge, UK).

The size of MEPs evoked by each stimulus in the trains was measured peak-to-peak. Onset and end-latency of the CSP evoked by each stimulus in the train were taken at the end of the preceding MEP and the intersection of the averaged rectified signal with baseline indicating 80% of the background EMG level. The duration of CSP between these two points was computed automatically (Inghilleri et al. 1993).

Laboratory methods

[Ca2+]s and parathyroid hormone levels were measured as previously described (Carnevale et al. 2004).

Statistical analysis

All results are expressed as means ± SD. A one-way between-groups (healthy normocalcaemic subjects vs. chronic hypercalcaemic patients) ANOVA was used to test RMT values, MEP amplitude and CSP duration evoked by the first stimulus in the trains. Changes in MEP size and CSP duration during rTMS trains were tested by a one-way between-groups repeated measures ANOVA for the time-related data (main factor ‘number of stimuli’). Student's paired t test was used to compare the RMT, MEP amplitude and CSP duration values in the two patients studied before and after surgery, and in the healthy subjects tested before and after [Ca2+]s infusion. Correlations between Δ-MEP (amplitude difference between the tenth and first MEP in the train) and [Ca2+]s concentrations were assessed with the partial correlation coefficient. P values less than 0.05 were considered to indicate statistical significance.

Results

None of the procedures caused adverse effects in patients or healthy controls.

Effects of chronic hypercalcaemia

No difference was found in the RMT values, MEP amplitude and CSP duration evoked by the first stimulus in the train between groups (RMT: F(1.42)= 1.0, P = 0.3; MEP size: F(1.42)= 0.8, P = 0.3; CSP duration: F(1.42)= 0.4, P = 0.4) (Table 1, Fig. 1).

Table 1.

RMT values

RMT (% of the maximal stimulator output)
Healthy subjects 60.0 ± 9.5
Patients with chronic hypercalcaemia 62.7 ± 9.3
Patients with parathyroidectomy
 First patient
  Pre-surgery 65
  Post-surgery 67
 Second patient
  Pre-surgery 60
  Post-surgery 59
Acute hypercalcaemia
 Pre-infusion 64.5 ± 3.6
 Post-infusion 64.1 ± 7.5
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All values are expressed as means ± SD.

Figure 1. rTMS in patients with chronic hypercalcaemia and in healthy subjects.

Figure 1

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A, motor evoked potential (MEP) facilitation elicited by repetitive transcranial magnetic stimulation (rTMS) in patients with chronic hypercalcaemia and in healthy subjects. X-axis: number of stimuli in the train from the first to the tenth stimulus; Y-axis: MEP size expressed in millivolts. Each point represents the mean values ± SD. B, cortical silent period (CSP) lengthening elicited by repetitive transcranial magnetic stimulation (rTMS) in patients with chronic hypercalcaemia and in healthy subjects. X-axis number of stimuli in the train from the first to the tenth stimulus; Y-axis: CSP duration expressed in milliseconds. Each point represents the mean value ± SD.

Between-group repeated measures ANOVA testing MEP values during rTMS trains showed a significant effect of factor ‘group’ (F(1.42)= 9.0, P = 0.004), and ‘number of stimuli’ (F(9.378)= 5.2, P < 0.0001) with a significant interaction of factors ‘group’ and ‘number of stimuli’ (F(9.378)= 2.5, P = 0.007). MEP increased in size less in patients with chronic hypercalcaemia than in healthy subjects (Fig. 1A).

Between-group repeated measures ANOVA testing CSP values during rTMS trains showed a significant effect of factor ‘number of stimuli’ (F(9.378)= 24.8, P < 0.0001), with no significant interactions (F(9.378)= 1.2, P = 0.2). The CSP duration lengthened to a similar extent in patients with chronic hypercalcaemia and healthy controls (Fig. 1B).

Study after parathyroidectomy

In both patients, parathyroidectomy normalized [Ca2+]s levels. The RMT values, MEP amplitude and CSP duration evoked by the first stimulus in the train were similar before and after surgery (Table 1, Fig. 2). Despite the limitations of the data obtained in only two patients the parathyroidectomy seemed to improve the MEP amplitude facilitation (t test P < 0.0001, Fig. 2).

Figure 2. rTMS before and after surgical treatment.

Figure 2

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Motor evoked potential (MEP) facilitation in patient 1 (upper panel) and patient 2 (lower panel) elicited by repetitive transcranial magnetic stimulation (rTMS) before and after surgical treatment. X-axis: number of stimuli in the train from the first to the tenth stimulus; Y-axis: MEP size expressed in millivolts. Each point represent the mean value ± SD.

Effects of acute hypercalcaemia in healthy subjects

Calcium infusion left the RMT values, MEP amplitude and CSP duration evoked by the first stimulus in the train unchanged (Table 1, Fig. 3). A within subjects comparison showed that calcium infusion significantly decreased MEP facilitation compared to baseline values (P = 0.001; Fig. 3A), whilst it left unchanged the CSP lengthening (P = 0.1; Fig. 3B). Partial correlation coefficient showed a significant correlation between the Δ-MEP and [Ca2+]s concentration (r =−0.73, P = 0.01).

Figure 3. rTMS before and after acute hypercalcaemia.

Figure 3

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A, motor evoked potential (MEP) facilitation elicited by repetitive transcranial magnetic stimulation (rTMS) in healthy subjects before and after acute hypercalcaemia. X-axis: number of stimuli in the train from the first to the tenth stimulus; Y-axis: MEP size expressed in millivolts. Each point represents the mean values ± SD. B, cortical silent period (CSP) lengthening elicited by repetitive transcranial magnetic stimulation (rTMS) in healthy subjects before and after acute hypercalcaemia. X-axis: number of stimuli in the train from the first to the tenth stimulus; Y-axis: CSP duration expressed in milliseconds. Each point represents the mean value ± SD.

Discussion

We designed this study to investigate whether hypercalcaemia affects short-term synaptic plasticity as measured by 5 Hz-rTMS. We investigated the Ca2+induced effects on the RMT, MEP amplitude facilitation and CSP lengthening during 5 Hz-rTMS trains in patients with primary hyperparathyroidism and healthy subjects. Two patients with parathyroid adenoma were re-tested after surgical treatment. In a subgroup of six healthy subjects we tested the effects of acute hypercalcaemia and determined the possible correlation between MEP changes and [Ca2+]s concentrations. These results show that chronic and acute hypercalcaemia significantly affect short-term synaptic plasticity as tested by 5 Hz-rTMS. During rTMS, MEP amplitudes increased significantly less in patients with chronic hypercalcaemia than in healthy subjects. Control experiments in healthy subjects showed that the decreased MEP facilitation significantly correlated with the increased [Ca2+]s concentration. In the two patients retested after surgical treatment calcaemia normalized and rTMS induced a normal MEP amplitude facilitation. An interesting finding was that unlike the MEP facilitation, the CSP duration lengthened to a similar extent in patients and controls.

The finding that RMT and the size of the first MEP in the trains (evoked by stimuli at 120% RMT intensity) were similar between healthy controls and subjects with acute and chronic hypercalcaemia suggests that these parameters do not depend on changes in [Ca2+]e. It is possible that hypercalcaemia is unable to modulate intracortical excitatory phenomena involved in RMT and MEP amplitude (Di Lazzaro et al. 2003) or that, similarly to topiramate, carbamazepine and lidocaine (Inghilleri et al. 1993, 2006), hypercalcaemia probably affects phenomena sustained by repetitive neuronal firing (McLean & Macdonald, 1986; DeLorenzo et al. 2000).

There are several possible explanations for the lack of MEP facilitation during the train of stimulation in hypercalcaemic patients. First, the 5 Hz-rTMS induced MEP facilitation that we observed in healthy subjects closely resembles short-term synaptic enhancement (Bliss & Collengridge, 1993; Castro-Alamancos & Connors, 1996). We therefore speculate that the lack of MEP facilitation reflects altered short-term synaptic enhancement. A small decrease in [Ca2+]e also leads to increased synaptic excitability and burst firing that may enhance long-term potentiation, pain transmission, epileptogenesis and neuronal damage, and decrease anaesthetic potency (Wang et al. 2004). Conversely, increases in [Ca2+]e have the opposite effect on these processes (Wang et al. 2004). During hypercalcaemia, the increased Ca2+ influx through postsynaptic NMDA receptors might down-regulate NMDA receptors or alternatively stimulate intracellular signalling or a retrograde messenger thus reducing synaptic transmission in presynaptic terminals and consequently decreasing the MEP facilitation.

A second hypothesis is that presynaptic NMDA receptors (preNMDARs; Corlew et al. 2008) could mediate a prominent form of plasticity, spike timing-dependent LTD (tLTD) regulating presynaptic neurotransmitter release probability (Corlew et al. 2008). PreNMDAR-dependent tLTD requires postsynaptic calcium elevation and is expressed as a reduction in the probability of neurotransmitter release, involving a retrograde signal (Nevian & Sakmann, 2006). Thus, the lack of MEP facilitation during hypercalcaemia could be related to preNMDAR-induced synaptic depression.

A further contribution to the lack of MEP facilitation may come from a hypercalcaemia-induced decrease in Na+ current. This hypothesis receives support from studies on rat thalamic neurons showing a shift in the voltage dependence of voltage-activated Na+ channels (Formenti et al. 2001), and from our previous results showing that drugs acting as sodium-channel blockers, such as lidocaine, carbamazepine and topiramate, abolish the normal rTMS-induced MEP facilitation (Inghilleri et al. 2004, 2005, 2006). Studies investigating the mechanisms underlying the inverse relationship between volley activity and [Ca2+]e concentration in the entorhinal cortex and hippocampal pyramidal neurons suggest that the decreased burst firing during hypercalcaemia may result from a change in the properties of the slow sodium current (Su et al. 2001). These authors showed that [Ca2+]e regulates burst firing by decreasing Na+ current.

The normal MEP amplitude facilitation induced by rTMS in the two patients studied after surgery makes it unlikely that the lack of a normal MEP facilitation during hypercalcaemia reflects excitotoxic mechanisms (Deshpande et al. 2008) and/or neuronal death.

Finally, the similar duration of the CSP evoked by the first stimulus in the train and CSP lengthening in patients with hypercalcaemia and healthy subjects argues against a possible imbalance between GABA-mediated and glutamate-mediated neurotransmission. The unchanged RMT and first MEP in the rTMS train makes it unlikely that the lack of a normal MEP facilitation reflects prolonged depression of cortical excitatory interneuronal activity. Our findings that chronic and acute hypercalcaemia left the CSP duration unchanged are in line with the previously reported data suggesting that the mechanisms responsible for the CSP lengthening during rTMS-trains differ from those underlying short-term synaptic potentiation (Berardelli et al. 1999).

Our findings on the rTMS-induced MEP facilitation may help to understand the mechanisms underlying neuronal dysfunctions during hypercalcaemia, suggesting that ionized calcium modulates neurotransmission by altering short-term synaptic plasticity possibly by acting on NMDA receptors or depressing Na+ current. rTMS could be useful to evaluate the CNS function during hypercalcaemia, especially in asymptomatic patients, and to provide further insight into the brain mechanisms regulating memory and learning.

Glossary

Abbreviations

[Ca2+]s

serum ionized calcium concentration

CSP

cortical silent period

FDI

first dorsal interosseous

M1

primary motor cortex

MEP

motor evoked potential

NMDA

N-methyl d-aspartate

RMT

resting motor threshold

rTMS

repetitive transcranial magnetic stimulation

Author contributions

The experiments were performed in the laboratory of the Department of Neurological Sciences, ‘Sapienza’ University of Rome. Conception and design of the experiments: S.M. and M.I. Collection, analysis and interpretation of data: E.I., F.G., M.L.M., A.S., E.R. and F.P. Drafting the article or revising it critically for important intellectual content: E.I., F.G., S.F. and M.I. All authors approved the final version of the manuscript.

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