Magnesium carbonate for phosphate control in patients on hemodialysis . A randomized controlled trial Background Magnesium salts bind dietary phosphorus , but their use in renal patients is limited due to their potential for causing side effects . The aim of this study was to evaluate the efficacy and safety of magnesium carbonate -LRB- MgCO3 -RRB- as a phosphate-binder in hemodialysis patients . Introduction Normalization of the serum phosphate level is the cornerstone of medical protocols aimed at preventing and treating secondary hyperparathyroidism . Moreover , it has been shown that elevated serum levels of phosphate and the calcium -- phosphate product -LRB- Ca × P -RRB- play an important role in the development of extraosseous calcifications and are associated with increased mortality in hemodialysis patients -LSB- 1 , 2 -RSB- . The ingestion of phosphate-binding agents in conjunction with dietary phosphate restriction and its adequate removal by dialysis are the cornerstones of serum phosphate control in end-stage renal disease -LRB- ESRD -RRB- patients . However , four decades after the introduction of chronic hemodialysis in early 1960s , we have not yet found the ideal phosphate binder -LRB- s -RRB- in terms of combined efficacy , safety and low cost . Aluminum and calcium salts and non-aluminum and non-calcium agents , such as sevelamer and lanthanum carbonate , all have advantages and disadvantages -LSB- 3 -RSB- . Magnesium-containing agents are aluminum - and calcium-free and are inexpensive phosphate-binders and , to date , their potential has not been explored extensively . In studies involving small series of both hemodialysis and peritoneal dialysis patients , magnesium carbonate -LRB- MgCO3 -RRB- and magnesium hydroxide -LSB- Mg -LRB- OH -RRB- 2 -RSB- have been administered either alone or in combination with calcium salts with good results -LSB- 4 -- 10 -RSB- . However , these compounds are not widely used in ESRD patients because nephrologists have an inordinate fear of hypermagnesemia and the belief that Mg administration frequently is accompanied by gastrointestinal disorders . We carried out this study in hemodialysis patients to evaluate the efficacy and safety of MgCO3 as a phosphate-binder when given with a concurrent low dialysate magnesium solution . The control of serum phosphate in the two groups of patients was the primary outcome , while secondary outcomes were changes in serum calcium , magnesium , Ca × P and PTH levels and changes in bowel movements . Subjects and methods Patients and study design Stable ESRD patients on maintenance hemodialysis in our renal unit participated in the study . The protocol of this project was approved by the Ethics Committee of the hospital . Exclusion criteria were : age < 18 years , hemodialysis for less than 6 months , psychiatric or other disorders leading to non-compliance , unlikeliness to continue hemodialysis for more than 6 months in the same facility , critical illness at the time of recruitment , previous parathyroidectomy , severe hyperparathyroidism -LSB- serum intact parathyroid hormone -LRB- iPTH -RRB- > 500 pg/ml -RSB- , normal serum phosphate -LRB- < 5.5 mg/dl -RRB- without phosphate-binders , diseases resulting in diarrhea and the lack of informed consent . A total of 54 patients met the criteria and were approached for enrolment . The inclusion period lasted 2 months , between March 2 and April 29 , 2006 . Enrolled patients signed an informed consent and thereafter entered a 4-week washout period during which we withdrew all phosphate-binders as well as vitamin D medications . After the washout phase , three patients were removed because they had serum phosphate levels lower than 5.8 mg/dl ; the remaining 51 patients were allocated to receive either MgCO3 tablets -LRB- MgCO3 group -RRB- or calcium carbonate tablets -LRB- CaCO3 group -RRB- for 6 months . We chose CaCO3 instead of calcium acetate because the latter is not commercially available in Greece . Four patients did not agree to consume MgCO3 but did agree to participate by taking their standard binder of CaCO3 ; we allocated these patients to the CaCO3 group , whereas the remainder of the patients were randomly allocated with a ratio 1:1 to either the CaCO3 -LRB- 21 randomly assigned patients plus 4 = 25 patients -RRB- or to the MgCO3 -LRB- 26 -RRB- group . Each MgCO3 tablet contained 250 mg MgCO3 , which is equivalent to 71 mg of elemental magnesium , and each CaCO3 tablet contained 420 mg of CaCO3 equivalent to 168 mg of elemental calcium . All patients were on the same standard dialysis schedule -LRB- three times weekly × 4 h -RRB- , and in all of the patients the delivered dose of hemodialysis , as calculated by applying the single pool Kt/Vurea index using the second-generation formula of Daugirdas -LSB- 11 -RSB- , , was ≥ 1.35 . In both groups , calcium concentration in the dialysate bath was 1.50 mmol/l , whereas magnesium concentration was 0.48 mmol/l in the CaCO3 group and 0.30 mmol/l in the MgCO3 group . The National Kidney Foundation -LRB- NKF -RRB- suggests a bath calcium dialysate concentration of 1.25 mmol/l -LRB- based on opinion , not on evidence -RRB- . We used a bath concentration 1.50 mmol/l because we wanted to avoid episodes of hypocalcemia , particularly in the MgCO3 group . The patients should be more susceptible to manifest hypocalcemia since they did not receive vitamin D . The starting dose of both phosphate-binders were three tablets of MgCO3 or CaCO3 daily ; the dose was adjusted thereafter according to the serum phosphate values : weekly for the first month and then monthly . The dosage of the study drug was increased to one or two tablets per meal as required to achieve the target of serum phosphate level ≤ 5.5 mg/dl . Based on our clinical experience , to achieve adequate control of serum phosphate we set the maximum daily dose of CaCO3 to 3780 mg -LRB- nine tablets -RRB- , which is equivalent to 1512 mg of elemental calcium , and the maximum daily dose of MgCO3 to 2250 mg -LRB- nine tablets -RRB- , which is equivalent to 639 mg of elemental magnesium . Each patient 's full biochemical profile was obtained at baseline , then weekly during the first month and monthly thereafter . Parathyroid hormone was measured at baseline and then at monthly intervals . If a patient developed hypercalcemia -LRB- serum Ca > 10.5 mg/dl -RRB- , the daily dose of CaCO3 was reduced by one or two tablets . The same was done in patients with severe hypermagnesemia , which is defined as a serum magnesium level > 3.5 mg/dl . If severe hypermagnesemia persisted for more than 3 weeks , the administration of MgCO3 was stopped , and the patient was dropped from the study . No patient received vitamin D or a calcimimetic agent during the study . Serum total calcium values were corrected to the serum albumin values . Statistical analysis The laboratory values were expressed as mean -LSB- ± one standard deviation -LRB- SD -RRB- -RSB- . Student 's two-tailed unpaired t test was used to compare values between the two groups of patients at baseline and at 6 months . We used repeated measures of analysis of variance -LRB- repeated ANOVA method -RRB- to test for differences between the two treatment groups in average values of calcium , phosphate , Ca × P , magnesium , alkaline phosphatase -LRB- ALP -RRB- and PTH over time -LRB- time-averaged mean value differences -RRB- . The chi-square test was applied to determine differences in the prevalence of laboratory data . Significance was set at a P level of < 0.05 . Results Of the 26 patients enrolled in the MgCO3 group , one dropped out due to non-compliance . Of the remaining 25 patients , two -LRB- 8 % -RRB- discontinued ingestion of MgCO3 and dropped out : one -LRB- 4 % -RRB- because of persistent diarrhea , and one -LRB- 4 % -RRB- because of recurrent hypermagnesemia . Of the 25 patients in the CaCO3 group ; five were removed from the study -LRB- two received a kidney transplant , one died -LRB- pneumonia -RRB- , one suffered a stroke and was unable to swallow tablets and one moved to another hospital -RRB- . The use of phosphate-binders and vitamin D by the patients before the washout period is given in Table 1 . Patients ' mean serum values at baseline and at the end of the follow-up period are shown in Tables 2 and 3 . The monthly follow-up of the mean biochemical parameters are shown in Figs. 1 -- 4 . The mean Kt/Vurea was 1.379 ± 0.026 in the MgCO3 and 1.381 ± 0.027 in the CaCO3 group . Table 1Patients ' data in terms of the use of phosphate-binders and vitamin D before the washout periodMgCO3 group -LRB- n = 25 -RRB- CaCO3 group -LRB- n = 21 -RRB- Vitamin D11/258/21Phosphate binders25/2521/21 CaCO31916 Sevelamer24 CaCO3 + sevelamer41Table 2Mean serum values at baselineMgCO3 groupCaCO3 groupP value -LRB- t test -RRB- Age -LRB- years -RRB- 63.2365.32 P = nsSD12 .1911.68 Calcium -LRB- mg/dl -RRB- a9 .429.14 P = nsSD0 .540.43 Phosphorous -LRB- mg/dl -RRB- 6.636.58 P = nsSD0 .860.88 Ca × P product -LRB- mg/dl -RRB- 262.6260.08 P = nsSD10 .368.35 Magnesium -LRB- mg/dl -RRB- 2.382.36 P = nsSD0 .280.29 ALP -LRB- IU/l -RRB- 7686P = nsSD3735Intact PTH -LRB- pg/ml -RRB- 316296P = nsSD182157SD , Standard deviation ; ALP , alkaline phosphatase ; PTH , parathyroid hormone ; ns , not significantaSerum total calcium level corrected to serum albuminTable 3Mean values at 6 monthsMgCO3 groupCaCO3 groupP value -LRB- t test -RRB- Calcium -LRB- mg/dl -RRB- a8 .979.72 t = 2.16 SD0 .570.42 P < 0.05 Phosphorous -LRB- mg/dl -RRB- 5.125.28 t = 0.49 SD0 .700.74 P = NSCa × P product -LRB- mg/dl -RRB- 246.0451.38 t = 0.30 SD7 .657.75 P = NSMagnesium -LRB- mg/dl -RRB- 2.592.40 t = 1.59 SD0 .430.41 P = NSALP -LRB- IU/l -RRB- 8984t = 0.46 SD2826P = NSIntact PTH -LRB- pg/ml -RRB- 251212t = 0.42 SD118198P = NSaSerum total calcium corrected to serum albuminFig . 1Monthly follow-up of serum phosphate -LRB- sP -RRB- Fig. 2Monthly follow-up of serum calcium -LRB- sCa -RRB- Fig. 3Monthly follow-up of serum Ca × P product -LRB- SCa × P -RRB- Fig. 4Monthly follow-up of serum PTH -LRB- siPTH -RRB- The mean daily dose of CaCO3 was 6.76 tablets -LRB- range 3 -- 9 -RRB- containing a total of 2839 mg -LRB- range 1260 -- 3780 -RRB- of CaCO3 , which is equivalent to 1136 mg of elemental calcium -LRB- range 504 -- 1512 mg -RRB- The mean daily dose of MgCO3 was 6.21 tablets -LRB- range 3 -- 9 -RRB- containing a total of 1552 mg -LRB- range 750 -- 2,250 -RRB- of MgCO3 , which is equivalent to 441 mg of elemental magnesium -LRB- range 213 -- 639 mg -RRB- . A Shapiro -- Wilk test did not indicate any evidence against the normality assumption for the distribution of calcium , phosphate , Ca × P , magnesium , ALP and PTH levels within the two groups -LRB- CaCO3 and MgCO3 -RRB- at any time period during the follow-up . The significance level for the normality tests was set to a = 0.001 . Average values of the biochemical data during months 1 -- 6 are shown in Table 4 . The initial mean serum phosphate levels were 6.63 mg/dl in the MgCO3 group and 6.58 mg/dl in the CaCO3 group -LRB- P = ns -RRB- , while at the end of the study serum phosphate values were 5.13 and 5.26 mg/dl in the MgCO3 and CaCO3 groups respectively -LRB- P = ns ; Tables 2 , 3 -RRB- . Time-averaged mean serum phosphate values were 5.47 mg/dl in the MgCO3 group and 5.29 mg/dl in the CaCO3 group -LRB- P = ns ; Table 4 -RRB- . Serum phosphate levels decreased by 23 % in the MgCO3 group and by 19 % in the CaCO3 group -LRB- P = ns -RRB- . At the end of the study 17 of 23 -LRB- 74 % -RRB- patients in the MgCO3 and 13 of 20 -LRB- 65 % -RRB- of the CaCO3 group , -LRB- χ2 = 0.10 , P = ns -RRB- had serum phosphate values within the range recommended by the Kidney Disease Outcomes Quality Initiative -LRB- K/DOQI -RRB- guidelines -LRB- upper threshold of 5.5 mg/dl -RRB- -LRB- Table 5 -RRB- . Table 4Average serum values during months 1 -- 6 of the follow-up periodMgCO3 groupCaCO3 groupP value -LRB- t test -RRB- Calcium -LRB- mg/dl -RRB- a9 .139.60 P < 0.001 SD0 .530.45 Phosphorous -LRB- mg/dl -RRB- 5.475.29 P = nsSD0 .810.93 Ca × P product -LRB- mg/dl -RRB- 250.3550.70 P = nsSD7 .758.07 Magnesium -LRB- mg/dl -RRB- 22.572.41 P = nsSD0 .410.32 ALP -LRB- IU/l -RRB- 8880P = nsSD3227Intact PTH -LRB- pg/ml -RRB- 285231P < 0.01 SD161177aSerum total calcium corrected to serum albuminTable 5Patients with laboratory values within the Kidney Disease Outcomes Quality Initiative -LRB- K/DOQI -RRB- guideline range at 6 monthsMgCO3 group -LRB- n , % -RRB- CaCO3 group -LRB- n , % -RRB- χ2 , P valueCalcium 17/23 -LRB- 73.91 -RRB- 5/20 -LRB- 25 -RRB- χ2 = 8.42 , P < 0.01 Phosphorous17/23 -LRB- 73.91 -RRB- 13/20 -LRB- 65 -RRB- χ2 = 0.10 , P = nsCa × P product20/23 -LRB- 86.95 -RRB- 14/20 -LRB- 70 -RRB- χ2 = 0.99 , P = nsPTH11/23 -LRB- 47.82 -RRB- 8/20 -LRB- 40 -RRB- χ2 = 0.79 , P = ns Mean serum Ca values at baseline were 9.42 mg/dl in the MgCO3 group and 9.14 mg/dl in the CaCO3 group -LRB- P = ns -RRB- -LRB- Table 2 -RRB- . Time-averaged mean serum values were 9.13 mg/dl in the MgCO3 group and 9.60 in the CaCO3 group -LRB- P < 0.001 -RRB- -LRB- Table 4 -RRB- . At 6 months , these values were 8.97 and 9.72 mg/dl , respectively -LRB- P < 0.05 -RRB- -LRB- Table 2 -RRB- . Seventeen patients -LRB- 17/23 ; 74 % -RRB- who received MgCO3 and only 5/20 -LRB- 25 % -RRB- of those on CaCO3 had serum Ca values within the K/DQOI guidelines -LRB- χ2 = 8.42 , P < 0.01 -RRB- -LRB- Table 5 -RRB- . We encountered six episodes of hypercalcemia , defined as a serum calcium level > 10.5 mg/dl , in the CaCO3 group in comparison to one episode in the MgCO3 group . The two groups of patients had nearly equal values of serum Ca × P product at the beginning , at the end as well as during the period study -LRB- Tables 2 -- 4 -RRB- , with the MgCO3 group having 62.6 mg2/dl2 and the CaCO3 group having 60.1 mg2/dl2 -LRB- P = ns -RRB- -LRB- Table 1 -RRB- . Mean levels of Ca × P during months 1 -- 6 of the follow-up were similar -- 50.35 mg2/dl2 in the MgCo3 group and 50.70 mg2/dl2 in the CaCo3 group -LRB- P = ns -RRB- -LRB- Table 4 -RRB- ; at the end of the study , the corresponding values were 46.0 and 51.4 mg2/dl2 -LRB- P = ns -RRB- -LRB- Table 3 -RRB- , whereas 20/23 -LRB- 87 % -RRB- and 14/20 -LRB- 70 % -RRB- patients , respectively , had Ca × P product below the upper limits of K/DQOI recommendations -LRB- P = ns -RRB- -LRB- Table 5 -RRB- . Starting mean levels of serum iPTH were similar in both groups -- 316 ± 182 pg/ml in the MgCO3 group and 296 ± 157 pg/ml in the CaCO3 group -LRB- P = ns -RRB- -LRB- normal range 10 -- 65 pg/ml -RRB- -LRB- Table 2 -RRB- . During the 6-month follow-up period , average iPTH levels were significantly higher in the MgCO3-treated patients -LRB- 285 pg/ml -RRB- than in those treated with CaCO3 -LRB- 231 pg/ml -RRB- -LRB- P < 0.01 -RRB- -LRB- Table 4 -RRB- . However , at the end of the study , those levels did not differ significantly -- 251 ± 118 and 212 ± 198 pg/ml , respectively -LRB- P = ns -RRB- -LRB- Table 3 -RRB- . In terms of PTH levels , there was no statistically significant difference between the CaCO3 group and the MgCO3 group -- 29 versus 21 % , respectively -LRB- χ2 = 0.11 , P = ns -RRB- . Moreover , ten of 23 -LRB- 43 % -RRB- patients in the MgCO3 group and nine of 20 -LRB- 45 % -RRB- in the CaCO3 group had initial levels of iPTH above 300 pg/ml ; in three of these ten patients -LRB- 30 % -RRB- of the MgCO3 group and five of the nine -LRB- 56 % -RRB- of the CaCO3 group , the iPTH decreased below 300 pg/ml -LSB- χ2 = 1.38 , P = ns ; 11/23 -LRB- 48 % -RRB- -RSB- . Eight of 20 patients -LRB- 40 % -RRB- in the CaCO3 group and six of 23 patients -LRB- 26 % -RRB- in the MgCO3 group -LRB- P = ns -RRB- had final values of iPTH below 150 pg/ml . The number of patients of both groups , patients who received MgCO3 , and eight of 20 -LRB- 40 % -RRB- patients who received CaCO3 who had serum phosphorus , calcium , Ca × P product and iPTH values at 6 months that fell within the range recommended by the K/DOQI guidelines are shown in Table 5 -LRB- χ2 = 0.79 , P = ns -RRB- . During the follow-up period the average serum Mg levels were slightly -- but not significantly -- higher in the MgCO3 group than in the CaCO3 group : 2.57 vs. 2.41 mg/dl -LRB- P = ns -RRB- -LRB- Table 4 -RRB- . Similarly , at 6 months , these values were 2.59 and 2.40 mg/dl -LRB- P = ns -RRB- -LRB- Table 3 -RRB- . One patient of the 25 -LRB- 4 % -RRB- stopped taking MgCO3 because of recurrent high levels of serum magnesium -LRB- > 3.5 mg/dl , the upper threshold according to our protocol -RRB- . Two more patients manifested a transient elevation of serum magnesium -- from 3.18 to 3.36 mg/dl . No patient in the CaCO3 group had a serum magnesium > 3 mg/dl . Discussion This is the first study that compares MgCO3 with only one other phosphate-binder in hemodialysis patients . Our results show that MgCO3 administered for a period of 6 months has a good phosphate-binding ability , is well tolerated by most patients and is accompanied by a low incidence of side effects . O'Donovan et al. -LSB- 4 -RSB- described 28 patients on hemodialysis who were given magnesium chloride in place of oral aluminum hydroxide . These patients were also switched from a dialysate containing 0.85 mmol/l magnesium to one not containing any magnesium at all . After 24 months of treatment on this regimen , serum phosphate was effectively controlled in these patients . The researchers saw no evidence of increased secondary hyperparathyroidism . Delmez et al. -LSB- 5 -RSB- conducted a 10-week , prospective , randomized crossover study of 15 hemodialysis patients , who were on MgCO3 with a dialysate magnesium concentration of 0.25 mmol/l ; with this regimen , these investigators were able to reduce the CaCO3 dose and use a higher dose of calcitriol . Mean serum phosphate levels in the patients were similar with the MgCO3/CaCO3 combination as with the CaCO3 treatment alone -LRB- 5.7 ± 0.2 vs. 5.2 ± 0.2 mg/dl , respectively -RRB- , and there were no adverse gastrointestinal effects . Parsons et al. -LSB- 6 -RSB- described 32 continuous cycling peritoneal dialysis -LRB- CAPD -RRB- in patients who were dialyzed with magnesium-free dialysate and used a mixture of CaCO3 and MgCO3 as a phosphate-binder for over 1 year . These patients achieved satisfactory control of hyperparathyroidism , with normal serum calcium , phosphorous and magnesium concentrations . Other investigators have also shown that the use of magnesium-containing agents as phosphate-binders can provide effective control of serum phosphate and hyperparathyroidism and that serum magnesium levels remain within acceptable ranges -LSB- 7 -- 10 -RSB- . Spiegel et al. -LSB- 12 -RSB- recently compared a regimen of MgCO3 and CaCO3 versus one with calcium acetate and found that the two were equally effective as phosphate-binders . In our study , MgCO3 was well tolerated by most of our patients -- only two of the 25 patients -LRB- 8 % -RRB- of this group were removed from the study , one for diarrhea and the other for hypermagnesemia . A third patient complained initially of mild diarrhea and abdominal discomfort , but this resolved after the first week . In comparison , five patients in the CaCO3 arm complained of constipation , but none dropped out of the study . Serum phosphate levels after the 4-week wash-out period were 6.63 mg/dl in the MgCO3 group and 6.58 mg/dl in the CaCO3 group . These values are lower than those reported by other investigators : 7.7 mg/dl by Qunibi et al. -LSB- 13 -RSB- in the CARE study , 7.4 -- 7.7 mg/dl by Chertow et al. -LSB- 14 -RSB- in the Treat to Goal study and 6.6 -- 7.2 mg/dl by Asmus et al. -LSB- 15 -RSB- . However , in the recently presented preliminary results of the CARE 2 study -LSB- 16 -RSB- , patients ' mean serum phosphate values were 6.5 -- 6.6 mg/dl . Our values may have been lower because our patients adhered more closely to their diet , they were receiving an adequate dose of hemodialysis or they had neither marked hyperparathyroidism -LRB- siPTH < 500 pg/ml -RRB- nor did they receive vitamin D . The Mediterranean type of diet consumed by our population on the island of Crete is less likely to cause hyperphosphatemia . The serum phosphate level was reduced equally in both groups , and after the second month of treatment the mean values of serum phosphate in the two groups were comparable . -LRB- Table 3 ; Fig. 1 -RRB- . In terms of the biochemical findings , the main difference between the two groups was the levels of serum calcium . Hypercalcemia is the price one has to pay for adequate phosphate-binding control with calcium-containing binders ; the absence of hypercalcemia is the major advantage of magnesium-based phosphate-binders . We observed that patients receiving MgCO3 were more likely to have serum calcium levels within the K/DQOI guidelines -LSB- 17 -RSB- than those on CaCO3 . Both groups of patients achieved a mean serum Ca × P product of < 55 mg2/dl2 -LRB- Tables 3 , 4 -RRB- . Consequently , a significant proportion of patients had a Ca × P product within the K/DQOI recommendations -LRB- Table 5 -RRB- . The risk of severe hypermagnesemia is a major concern when magnesium salts are administered to hemodialysis patients . In such patients serum magnesium levels depend chiefly on the dialysate concentration of this ion , which standardly ranges between 0.45 and 0.50 mmol/l . In the MgCO3 group we used a low magnesium dialysate , 0.30 mmol/l , and this enabled us to avoid extreme hypermagnesemia and keep serum magnesium levels within acceptable ranges . Clinical symptoms and ECG disorders due to hypermagnesemia appear only when the level of serum magnesium > 4 mg/dl -LSB- 18 -RSB- . The ionized fraction that represents approximately 60 % of the total serum magnesium is the biologically active form of this element . Truttmann et al. -LSB- 19 -RSB- and Saha et al. -LSB- 20 -RSB- recently demonstrated that the ionized fraction of magnesium lower in HD patients than in individuals with normal renal function ; therefore , the incidence of ` real hypermagnesemia ' may be overestimated in these patients . Of note is that serum magnesium accounts for approximately 1 % of the total body magnesium since it is mainly an intracellular cation . Estimation of total body magnesium is based on the determination of intracellular magnesium -LRB- IcMg -RRB- levels in skeletal muscles or in peripheral lymphocytes -LSB- 21 -RSB- . Calculations on the levels of magnesium in these tissues in uremic patients have produced conflicting results , with positive or neutral or even a negative correlation with serum magnesium being found -LSB- 22 , 23 -RSB- . Although we did not examine the consequences of hypomagnesemia and high serum magnesium levels , various studies have shown that hypomagnesemia plays a significant role in the pathogenesis of cardiovascular diseases and that a high serum magnesium level may retard the development and/or acceleration of arterial atherosclerosis -LSB- 24 , 25 -RSB- . Meema et al. -LSB- 26 -RSB- first showed that ` hypermagnesemia might be associated with retardation or improvement of arterial calcifications in peritoneal dialysis patients ' . Izawa et al. -LSB- 27 -RSB- described a hemodialysis patient in whom soft-tissue calcifications resolved after treatment with a dialysate with a high concentration of magnesium . Two studies by our team -LSB- 28 , 29 -RSB- clearly demonstrated that the absence of mitral annular calcifications and a thinner carotid intima media thickness in hemodialysis patients both correlated with higher levels of serum and intracellular magnesium . In a previous study , we showed that both intracellular and serum magnesium concentrations were directly associated with 5-year survival in 94 hemodialysis patients of our unit -LSB- 30 -RSB- . One of the secondary objectives of the study was to investigate if MgCO3 effectively controls serum iPTH . Calcium carbonate was more effective than MgCO3 in decreasing serum iPTH . In the MgCO3-treated patients time-average mean values of iPTH during months 1 -- 6 were significantly higher than in those treated with CaCO3 -LRB- Table 4 -RRB- . However , the final levels of serum iPTH at 6 months did not differ significantly between the two groups . Furthermore , at the end of 6 months , a slightly higher number of patients -LRB- 48 % -RRB- in the MgCO3 group than in the CaCO3 -LRB- 40 % -RRB- group achieved serum iPTH values in the range of 150 -- 300 pg/ml . In the presence of almost equal serum P values in the two groups , we hypothesize that the relatively higher PTH reduction in the CaCO3 group was due to the significant higher concentration of serum calcium in this group . On the other hand , high levels of serum magnesium have a similar , but weaker , action in suppressing PTH secretion -LSB- 31 -RSB- . Figure 4 , which shows the monthly follow-up of serum iPTH levels , shows that the curve of the change in mean iPTH values is different in the MgCO3-treated patients in that the mean values increase during the first month of the treatment , subsequently falling -LRB- but slower than in the CaCO3 group -RRB- and finally , in the sixth month , they approach the mean iPTH values of the CaCO3 group . We speculate that the shape of this curve indicates that suppressive action of serum magnesium on the parathyroid glands is weaker but delayed compared to that of serum calcium . The number of patient who had final serum iPTH values of < 150 pg/ml , which could be associated with adynamic bone disease , did not differ in the two groups . However , the impact of the two regimens on the patients ' bone turn over was not included in the objectives of the study , so we did not obtain data associated with bone metabolism markers . Our experience suggests that a significant proportion of hemodialysis patients need more than one agent to achieve a satisfactory phosphate-binding . In such cases , MgCO3 could be if not the primary at least the second constituent of the phosphate-binding regimen , combined ideally with a calcium-containing salt . An additional advantage is that MgCO3 is much less expensive than the newest sevelamer HCL and lanthanum carbonate . The limitations of our study are : -LRB- 1 -RRB- it is a single-center study , although this has also a number of advantages ; -LRB- 2 -RRB- the number of the participant patients was not large , although it is one of the largest groups reported to date ; -LRB- 3 -RRB- the allocation of the patients to the two regimens was only partially random ; -LRB- 4 -RRB- the relatively low starting serum phosphate level in conjunction with the no vitamin D use means that the patients were not typical of most HD patients ; -LRB- 5 -RRB- we did not obtain data on the patients ' bone metabolism markers . In conclusion , our study showed that MgCO3 administered for a period of 6 months is an effective and inexpensive agent to control serum P levels in hemodialysis patients . Gastrointestinal disorders due to its use were minor , while its administration in combination with a low dialysate magnesium concentration reduces the risk of severe hypermagnesemia . Patients treated with MgCO3 had a mild suppression of PTH , an optimum regulation of Ca × P product , relatively low serum calcium and no episodes of hypercalcemia . We believe that this demonstration of the effectiveness of MgCO3 to bind phosphate warrants further investigation in a larger group of patients .

B I O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

end-stage renal disease
phosphate-binders


The first demonstration of lactic acid in human blood in shock by Johann Joseph Scherer -LRB- 1814 -- 1869 -RRB- in January 1843 Lactic acid was first found and described in sour milk by Karl Wilhelm Scheele -LRB- 1742 -- 1786 -RRB- in 1780 . The German physician -- chemist Johann Joseph Scherer -LRB- 1841 -- 1869 -RRB- demonstrated the occurrence of lactic acid in human blood under pathological conditions in 1843 and 1851 . In this article we honour the forgotten observations by Scherer and describe the influence of Scherer 's finding on further research on lactic acid at the end of the 19th century . We conclude that Scherer 's 1843 case reports should be cited as the first description of lactic acid in human blood after death and also as the first demonstration of lactic acid as a pathological finding in septic and haemorrhagic shock . Carl Folwarczny was , in 1858 , the first to demonstrate lactic acid in blood in a living patient . Introduction Lactic acid was first found and described in sour milk by the Swedish chemist Karl Wilhelm Scheele -LRB- 1742 -- 1786 -RRB- in 1780 -LSB- 1 -RSB- . The Swedish chemist Jöns Jakob Berzelius -LRB- 1779 -- 1848 -RRB- found lactic acid in fluid extracted from meat in 1808 -LSB- 2 , 3 -RSB- , and the German chemist Justus von Liebig -LRB- 1803 -- 1873 -RRB- , who established the world 's first school of chemistry at Giessen , proved that lactic acid was always present in muscular tissue of dead organisms -LSB- 4 -RSB- . In 1859 , Emil Heinrich du Bois-Reymond -LRB- 1818 -- 1896 -RRB- published several articles on the influence of lactic acid on muscle contraction -LSB- 5 -- 9 -RSB- . Araki and Zillessen found that if they interrupted oxygen supply to muscles in mammals and birds , lactic acid was formed and increased -LSB- 10 -- 14 -RSB- . This was the first demonstration of the relationship between tissue hypoxia and the formation of lactate . The occurrence of increased lactic acid in blood -LRB- hyperlactataemia -RRB- nowadays reflects severe illness , in which the increased blood lactate levels may result from both anaerobic and aerobic production or from a decreased clearance . It was the German physician -- chemist Johann Joseph Scherer who first demonstrated the occurrence of lactic acid in human blood under pathological conditions after death in 1843 and 1851 -LSB- 15 , 17 -RSB- , and Carl Folwarczny in 1858 who first demonstrated lactic acid in blood of a living patient . In this article we wish to honour Scherer 's forgotten observations and describe the influence of his finding on further research on lactic acid at the end of the 19th century . Biography of Johann Joseph Scherer Born on 18 March 1814 in Aschaffenburg , Germany , Scherer studied medicine , chemistry , geology and mineralogy at the university of Würzburg between 1833 and 1836 . He obtained his PhD in medicine and surgery in 1838 with a thesis entitled `` Versuche über die Wirkung einiger Gifte auf verscheidene Thierclassen '' -LRB- Experiments on the action of some poisons on several classes of animals -RRB- . He practised medicine in Wipfeld , but inspired by the chemist Ernst von Bibra -LRB- 1806 -- 1878 -RRB- he completed his studies in chemistry at the University of Munich between 1838 -- 1840 -LSB- 18 -RSB- . In 1840 he was employed at the laboratory of Justus Liebig at Giessen , and became professor at the medical faculty in 1842 , professor of organic chemistry in 1847 , and later professor of general , anorganic and pharmaceutical chemistry . His work especially concerned quantitative research on blood and urine in pathological conditions . In 1843 he published his book ` Chemische und Mikroskopische Untersuchungen zur Pathologie angestellt an den Kliniken des Julius-Hospitales zu Würzburg ' -LRB- Chemical and microscopic investigations of pathology carried out at the Julius Clinic at Würzburg -RRB- -LSB- 15 -RSB- -LRB- Fig . 1 -RRB- , in which he described 72 case reports , giving details on clinical course , diagnosis , and results obtained during autopsy and analysis of body fluids . Scherer died on 17 February 1869 -LSB- 18 -RSB- . Fig. 1Title page of Scherer 's 1843 book The 1843 cases In one chapter in his 1843 book entitled ` Untersuchungen von krankhaften Stoffen bei der im Winter 1842 -- 1843 in Würzburg und der Umgegend herrschenden Puerperal-Fieber-Epidemie ' -LRB- Investigations of pathological substances obtained during the epidemic of puerperal fever which occurred in the winter of 1842 -- 1843 in and around Würzburg -RRB- Scherer described the cases of seven young women who all died peripartum . One of the women , the 23-year-old primipara Eva Rumpel , gave birth to a healthy child on 9 January 1843 . The same night she developed a painfully swollen abdomen and became ill , feverish , and sweaty , with rapid pulse and severe thirst . The initiated treatment was bloodletting and clystering . The next evening she deteriorated , became delirious , with anxious breathing , a tense abdomen , cold extremities and rapid pulse , finally losing consciousness . Again , bloodletting followed . At 4:30 a.m. , 36 h after the onset of the first symptoms , she died . During autopsy , severe purulent endometritis , vaginal pus , pulmonary oedema , and shock liver and shock spleen were found . The blood that was obtained directly from the heart was chemically analysed , in which lactic acid was found . Most likely this unfortunate woman had died from a fulminant septic shock caused by group A haemolytic streptococci -LRB- Streptococcus pyogenes -RRB- . Scherer diagnosed this case as perimetritis with secondary peritonitis . Another patient , the 28-year-old , 7 months pregnant -LRB- second pregnancy -RRB- Margaretha Glück , was , after being icteric , nauseous , vomiting and complaining about epigastric pain for 8 days , admitted to the lying-in birth clinic on 6 February 1843 . Four days later she was transferred to the hospital with severe nosebleeds and generalised exanthema or purpura . In the evening she suffered from severe gastric bleeding and epistaxis , showing rapid pulse , cold extremities and dizziness . The next morning , she was transferred back to the birth clinic , where she gave birth to a premature child -LRB- 30 weeks -RRB- and suffered from a severe post-partum fluxus . She was again transferred to the hospital with the following symptoms : cold clammy skin , tachycardia , severe lochia and persistent exanthema or purpura , but without signs of an acute abdomen . During the night of February 11 , she became aphasic and restless , followed by chills and profound sweating . On the morning of February 13 , she further deteriorated and bilirubinuria was detected . The next day she was comatose , finally developed rattling breathing and convulsions . Death occurred during the following night . Autopsy revealed a small intracerebral haematoma , normal lungs without pulmonary oedema , ascites and an anaemic , foul smelling uterus filled with purulent and decayed tissue and pus . Blood was also obtained directly from the heart during autopsy and lactic acid was found . In this case we could think of a haemorrhagic shock and cerebral haemorrhage due to clotting disorders possibly resulting from either acute fatty liver of pregnancy/HELLP syndrome , idiopathic thrombocytopenic purpura , thrombotic microangiopathy -LRB- TTP/HUS -RRB- or DIC . The case was most likely complicated by a sepsis -LRB- endometritis -RRB- . Scherer himself diagnosed this case as septic endometritis . In the conclusions of his 1843 book , Scherer attached high importance to the fact that he found lactic acid in cases of puerperal fever , which he had not found before in healthy persons . He held the opinion that lactic acid was formed in blood during bodily deterioration in severe diseases like puerperal fever . Lactic acid was thus described for the first time in human blood and was demonstrated for the first time as a symptom of septic and haemorrhagic shock . In the same period a junior obstetrician in Vienna , Ignaz Philipp Semmelweis -LRB- 1818 -- 1865 -RRB- , discovered in 1847 that physicians carried infectious particles on their hands from the mortuary to the obstetrical clinic , causing puerperal fever and puerperal sepsis , and he introduced a successful method for its prevention . Louis Pasteur -LRB- 1822 -- 1894 -RRB- found in 1879 that infection with streptococci was the most important cause of puerperal fever -LSB- 16 -RSB- . The 1851 article Scherer worked closely with the famous pathologist Rudolf Virchow -LRB- 1821 -- 1902 -RRB- on several projects -LRB- Fig . 2 -RRB- . In 1851 Virchow performed an autopsy on a patient who had died from leukaemia and offered Scherer blood from this patient for analysis . The results of this analysis were published the same year in the ` Verhandlungen der Physikalisch-Medicinischen Gesellschaft in Würzburg ' -LSB- 17 -RSB- . Virchow and Scherer had previously studied the spleens of patients who died from leukaemia , and were curious if they could find the same results in the blood . Scherer reached the conclusion that : the blood of this patient contains : `` Ameisensäure , Essigsäure und Milchsäure , die gleichfalls von mir schon früher als in der Milzflüssigkeit vorkommend bezeichnet wurden '' -LRB- Formic acid , acetic acid , and lactic acid , as also found by me previously in fluids from the spleen -RRB- . Fig. 2Johann Joseph Scherer -LRB- left -RRB- and Rudolf Virchow -LRB- right -RRB- in 1849 Further research Scherer 's observations inspired others to conduct further research , primarily in patients with leukaemia -LSB- 19 -- 22 -RSB- , but also in patients with other conditions and diseases and in animal experiments with dogs and rabbits -LSB- 23 -RSB- . While Scherer found lactic acid in blood obtained after death during autopsy , Mosler and Körner -LSB- 19 -RSB- mention an observation made by Carl Folwarczny , published in the Allgemeinen Wiener Medicinischen Zeitung in 1858 , where blood was withdrawn from a leukaemia patient during life , analysed according to Scherer 's method , and found positive for lactic acid . In addition , Carl Folwarczny described in 1863 in his ` Handbuch der Physiologischen Chemie ' -LSB- 24 -RSB- that lactic acid can be found in the blood of patients with leukaemia , septicaemia -LRB- pyaemia -RRB- and in conditions leading to septicaemia like puerperal fever , the latter probably after Scherer 's observations . In an extensive article , the Berliner physician Georg Salomon -LSB- 25 -RSB- , who had serious doubts that the occurrence of lactic acid in blood was mostly related to leukaemia , proved in 1878 that lactic acid was also present in the blood of patients who were suffering and died from other diseases . He studied blood obtained during autopsy from cadavers , but also blood from patients obtained by bloodletting or cupping , and in some cases he compared the blood before and after death . He was able to demonstrate lactic acid in the blood of patients suffering from leukaemia , -LRB- pernicious -RRB- anaemia , congestive heart failure , chronic obstructive pulmonary disease , pleuritis , pericarditis , pneumonia and several solid malignant tumours . Gaglio -LSB- 26 -RSB- is often erroneously mentioned as the first author to find lactic acid in blood -LSB- 27 -- 29 -RSB- . He was able to demonstrate lactic acid in fresh arterial blood withdrawn from dogs and rabbits after bloodletting . Berlinerblau -LSB- 30 -RSB- confirmed these observations in mammalian and venous human blood . Both Gaglio and Berlinerblau , however , neglected previous research , as indignantly described by Salomon in 1888 -LSB- `` Ich erlaube mir , den Inhalt meiner Arbeiten , die von Gaglio nur ganz flüchtig , von Berlinerblau gar nicht berührt sind , in Kürze zu reproduciren '' -LRB- I take the liberty of summarizing the contents of my work , which was mentioned only briefly by Gaglio and not at all by Berlinerblau -RRB- -RSB- -LSB- 31 -RSB- . The Japanese chemist Trasaburo Araki showed that the amount of lactic acid in exhausted muscle results from muscle activation -LSB- 11 -RSB- . Irisawa -LSB- 32 -RSB- , inspired by the results obtained by Salomon and Gaglio , obtained fresh blood of 11 dying patients with serious conditions . In six cases he found hyperlactataemia , in four cases normal values . He speculated on the aetiology of hyperlactataemia , the most plausible cause being the severe hypoxia during the dying process . In an experiment in which he made a dog anaemic for several days , he found a rise in lactic acid levels during the time leading up to death . In Cambridge -LRB- UK -RRB- , Walter Morley Fletcher -LRB- 1873 -- 1933 -RRB- and Frederick Gowland Hopkins -LRB- 1861 -- 1947 -RRB- worked together on the metabolic changes occurring in muscular contractions and rigor mortis under anaerobic conditions , and found that lactate was the product of carbohydrate metabolism -LSB- 33 -RSB- . Their classic 1907 paper demonstrated rigorously that muscle contraction is accompanied by the anaerobic formation of lactic acid , which is removed aerobically , at a rate depending on the level of exposure to oxygen -LSB- 34 -RSB- . Poul Astrup and John Severingshaus mentioned Scherer 's 1851 article as first demonstration of lactic acid in blood , but overlooked the 1843 cases and Folwarczny 's work -LSB- 35 -RSB- . In conclusion , Scherer 's 1843 case reports -LSB- 15 -RSB- should be cited as the first description of lactic acid in human blood and also as the first demonstration of lactic acid as a pathological finding in septic and haemorrhagic shock . Folwarczny , in 1858 , was the first to demonstrate lactic acid in blood in a living patient .

O O O O B I O O O O B O B I I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O B O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I O O O O O O O O B O O O O O O O O O O O B I O O O O O O O

lactic acid
lactate
shock
leukaemia
johann joseph scherer


The effect of age on task-related modulation of interhemispheric balance Normal aging is associated with less lateralised task-related activation of the primary motor cortices . It has been hypothesized , but not tested , that this phenomenon is mediated transcallosaly . We have used Transcranial Magnetic Stimulation to look for age-related changes in interhemispheric inhibition -LRB- IHI -RRB- . Thirty healthy individuals -LRB- aged 19 -- 78 years -RRB- were studied using a paired-pulse protocol at rest and during a low-strength isometric contraction with the right hand . The IHI targeting the right motor cortex was assessed at two intervals , 10 ms -LRB- IHI10 -RRB- and 40 ms -LRB- IHI40 -RRB- . The corticospinal excitability of the left hemisphere was assessed by means of input -- output curves constructed during voluntary construction . Age was not correlated with IHI10 or IHI40 at rest . During muscle contraction IHI tended to increase at both intervals . However , this increase in IHI during the active condition -LRB- changeIHI -RRB- was less evident with advancing age for the 40 ms interval -LRB- r = 0.444 , P = 0.02 -RRB- ; in fact a degree of disinhibition was often present . There was no correlation between age and changeIHI10 . Age was negatively correlated with the area under the recruitment curve -LRB- r = − 0.585 , P = 0.001 -RRB- and the size of the maximum MEP collected -LRB- r = − 0.485 , P = 0.007 -RRB- . ChangeIHI and measures of corticospinal excitability were not intercorrelated . In conclusion , task-related increases in interhemispheric inhibition seem to diminish with advancing age . This phenomenon is specific for long-latency IHI and may underlie the age-related bihemispheric activation seen in functional imaging studies . The mechanism underlying changes in IHI with advancing age and the association with changes in corticospinal excitability need further investigation . Introduction Physical performance declines with increasing age -LRB- Hackel et al. 1992 ; Smith et al. 1999 -RRB- . Although age-related changes in muscular -LRB- Vandervoort 2002 -RRB- and neural architecture -LRB- Dorfman and Bosley 1979 ; Haug and Eggers 1991 ; Madden et al. 2004 -RRB- are an important cause of this decline , there is increasing interest in the role of functional alterations occurring throughout the motor system . Excitation -- contraction uncoupling -LRB- Delbono et al. 1995 -RRB- , motor unit remodelling -LRB- Wang et al. 1999 -RRB- , changes in the agonist -- antagonist activation pattern -LRB- Hortobagyi and Devita 2006 -RRB- and reorganization of the central motor pathways -LRB- Kido et al. 2004 ; Ward and Frackowiak 2003 ; Minati et al. 2007 -RRB- are all areas currently under study . Understanding the mechanisms underlying these phenomena will aid differentiation between inevitable functional failure and potential compensatory strategies which in turn may allow the development strategies to combat this age-related decline -LRB- Delbono 2003 -RRB- . Functional imaging has been used to assess age-dependent changes in the cerebral motor system in humans -LRB- for review see Ward 2006 -RRB- . In general , motor task-related brain activation is seen in a wider network with advancing age . The exact pattern of age-related change depends on the task being performed . However , it has been repeatedly shown that in older individuals there is increased bihemispheric activation during the execution of motor tasks that in younger individuals involve mainly lateralized processing . In particular , with advancing age there is less de-activation of the primary motor cortex -LRB- M1 -RRB- ipsilateral to the moving hand -LRB- Ward and Frackowiak 2003 ; Naccarato et al. 2006 ; Ward et al. 2007 -RRB- . It has been suggested , but not tested , that the underlying mechanism for this phenomenon involves changes in interhemispheric connections between the motor cortices . Transcranial magnetic stimulation -LRB- TMS -RRB- can be used to study interhemispheric connectivity between the motor cortices . At rest , this connectivity consists primarily of an inhibitory effect -LRB- interhemispheric inhibition , IHI -RRB- with a latency of 6 -- 50 ms -LRB- Ferbert et al. 1992 ; Di Lazzaro et al. 1999 ; Daskalakis et al. 2002 ; Chen 2004 -RRB- . This tonic IHI is modulated and follows a specific time course during preparation and execution of voluntary movement -LRB- Murase et al. 2004 ; Duque et al. 2005 , 2007 -RRB- . During the execution of an isometric muscle contraction , the IHI -LRB- at 10 ms latency -RRB- targeting the M1 ipsilateral to the moving hand has been shown to increase -LRB- Ferbert et al. 1992 -RRB- . This `` extra '' inhibition is in keeping with the primarily unilateral activation pattern seen in imaging studies of movement and has been interpreted as a means of minimizing mirror activity -LRB- Leocani et al. 2000 ; Duque et al. 2005 -RRB- . Task-related changes in longer latency IHI , i.e. 40 ms , have not been studied in detail but there is some evidence that they may be distinct to the ones seen in short latency IHI -LRB- Chen et al. 2003 -RRB- . Previous TMS studies have shown that there is reduction of activity in the intracortical inhibitory circuits in the elderly -LRB- Peinemann et al. 2001 ; Hortobagyi et al. 2006 -RRB- . It has been suggested that reduced inhibition represents a mechanism to compensate for the deleterious effects of aging on several levels of the motor system including the primary motor cortex -LRB- Pitcher et al. 2003 ; Oliviero et al. 2006 -RRB- but these notions remain mainly hypothetical -LRB- Wassermann 2002 -RRB- . The main purpose of this study was to investigate whether normal aging has an effect on the task-related modulation of IHI measured at two different latencies , 10 and 40 ms. We hypothesized that with increasing age there would be less extra activation in the inhibitory circuits targeting the M1 ipsilateral to the moving hand . In order to gain some insight of the mechanisms and the physiological meaning of these changes we also performed measures of corticospinal excitability on the side contralateral to the moving hand and looked for correlations with age and IHI measures . Methods Subjects Thirty healthy right-handed volunteers -LRB- mean age 42.9 years , range 19 -- 78 ; 30 % female -RRB- participated in the study after giving informed consent . They reported no history of neurological illness , psychiatric history , vascular disease or hypertension and they were not taking regular medication . The study was approved by local Ethics Committee . Transcranial magnetic stimulation Subjects were seated in an armchair with their eyes open . EMGs were recorded via Ag/AgCl electrodes placed over the First Dorsal Intersosseus -LRB- FDI -RRB- bilaterally , using a belly-tendon montage . Signals were filtered -LRB- 30 Hz to 10 kHz -RRB- , amplified using a Digitimer 360 -LRB- Digitimer Ltd , Welwyn Garden City , Herts. , UK -RRB- and stored on computer via a Power 1401 data acquisition interface -LRB- Cambridge Electronic Design Ltd , Cambridge , UK -RRB- . Analysis of data was carried out using Signal Software -LRB- Cambridge Electronic Design -RRB- . Two figure-of-eight coils connected to two monophasic Magstim 200 stimulators were used for the experiments -LRB- all Magstim Co. , UK -RRB- . A 70-mm coil was used for motor hot spot identification and threshold measurements on both sides of the brain . The motor hotspot was defined as the scalp location where TMS consistently resulted in the largest MEP . The resting motor threshold -LRB- RMT -RRB- was defined as the lowest intensity needed to evoke an EMG response of 50 μV in 50 % of the trials with the FDI relaxed ; the active motor threshold -LRB- AMT -RRB- was defined as the intensity which evoked a 200 μV EMG response in 50 % of the trials with a background FDI contraction of 10 -- 15 % of the maximum voluntary contraction -LRB- MVC -RRB- . For all studies requiring activation of the FDI , visual feedback was provided using an oscilloscope . A recruitment curve -LRB- RC -RRB- for the active MEP amplitude elicited in the left FDI was obtained using the 70 mm coil while the subjects maintained a background FDI contraction of 15 -- 20 % MVC . Ten MEPs were collected and averaged at the following stimulus intensities : 90 , 100 , 110 , 120 , 140 , 150 , 160 and 170 % AMT . The contraction level was tested by measuring the mean value of the rectified EMG in the 80 ms preceding the TMS pulse . The averaged peak-to-peak amplitude of the unrectified MEPs was then expressed as a ratio of the maximum peak-to-peak amplitude of the unrectified compound action potential -LRB- CMAP -RRB- evoked by supramaximal electrical stimulation of the ulnar nerve at the wrist using a Digitimer pulse stimulator -LRB- model DS7 -RRB- . Interhemispheric inhibition -LRB- IHI -RRB- was measured using a standardised paired-pulse paradigm -LRB- Ferbert et al. 1992 -RRB- . IHI is expressed as the reduction in the response to a suprathreshold TMS pulse -LRB- test -RRB- delivered to the M1 when another suprathreshold pulse is delivered to the contralateral M1 6 -- 50 ms earlier -LRB- conditioning -RRB- . Here , we concentrated on the IHI targeting the right M1 . Hence the conditioning pulse was given over the left M1 using the same 70-mm coil . For the test pulse a smaller 50 mm figure-of-eight coil was held over the right M1 ; this allowed us to accommodate two coils on the head of all the subjects without compromising the exact positioning of the coils over the motor hot-spot -LRB- Ferbert 1992 -RRB- . MEPs were measured from the left FDI . Ten single -LRB- test -RRB- and ten paired-pulse -LRB- conditioning + test -RRB- trials were randomly intermingled and averaged . IHI was defined as the conditioned/test MEP amplitude ratio , smaller values reflecting stronger IHI . Interstimulus intervals -LRB- ISIs -RRB- of 10 and 40 ms were studied in different blocks . IHI was initially measured at rest -LRB- restIHI10 and restIHI40 -RRB- . The stimulation intensity for both the conditioning and the test stimuli was adjusted to evoke an MEP of 1 -- 1.5 mV in the contralateral FDI muscle . For the active condition -LRB- activeIHI10 and activeIHI40 -RRB- the subjects were instructed to contract the right FDI to 15 -- 20 % of their MVC in response to an auditory cue preceding the conditioning stimulus by 600 ms. In this way , we made sure that the subject had reached the target level of background contraction for at least 200 ms before the conditioning pulse . This was to avoid measuring changes in IHI that are associated with the preparation of the movement rather than a steady isometric contraction -LRB- Duque et al. 2005 , 2007 -RRB- . EMG activity in the left FDI was also recorded and contaminated trials were rejected to avoid the confounding effect of mirror activity . The stimulation intensity both for the conditioning and test stimulus was the same as in the resting state , as in previous studies -LRB- Ferbert et al. 1992 -RRB- . The absolute values of activeIHI were then expressed as a ratio to the values at rest for the respective ISI -LRB- changeIHI10 and changeIHI40 -RRB- . ChangeIHI therefore reflects the change seen in the IHI targeting the right motor cortex when the right hand is active . Values < 1 reflect stronger inhibition , while values > 1 reflect less inhibition . Statistical analysis Analysis was performed using SPSS v. 14 -LRB- SPSS Inc. , USA -RRB- . Exploratory plotting and statistical tests -LRB- Shapiro-Wilk -RRB- confirmed normal distribution for most variables . Some of the variables were skewed by a single outlier and this could not be corrected by logarithmic transformations ; the outlier was therefore discarded from the dataset to allow use of parametric tests . Data obtained during the RC paradigm were plotted against the stimulation intensity . In most subjects the resulting curves were sigmoidal in shape . Two representative examples , one from a young and one from an old subject , are shown in Fig. 1 . The area under the RC -LRB- AUC -RRB- was calculated using the method of trapezoid integration to provide a summary measure of the corticospinal output across all stimulation intensities . Data points were then fitted in the Boltzmann sigmoidal model based on the modified Levenberg -- Marquardt nonlinear least-mean-squares algorithm -LRB- Press et al. 1986 -RRB- . This function is often used to provide parameter estimates for RCs -LRB- Capaday et al. 1999 ; Devanne et al. 1997 -RRB- . The data were best fitted by a 4-parameter equation in which the amplitude of the MEP at a given stimulation intensity -LRB- I -RRB- is estimated as : MEPmax and MEPmin represent the maximum and minimum MEP amplitude , respectively ; I50 represents the stimulation intensity required to get a response 50 % of the maximum . The inverse of the slope parameter -LRB- 1/slope -RRB- is directly proportional to the maximal steepness of the curve , which occurs at I50 -LRB- Devanne et al. 1997 -RRB- . The R2 co-efficient of determination was greater than 0.89 in all subjects . Fig. 1Representative examples of the recruitment curves plotting the amplitude of the active MEPs against the stimulation intensity . The circles represent the collected data . The line represents the relation predicted by the Boltzmann model . The area under the curve -LRB- grey area -RRB- was calculated with the method of trapezoid integration using the actual data collected during the construction of the curves . CMAP , compound motor action potential , AMT , active motor threshold Pair-wise comparisons between different TMS measures were performed using paired t tests . Correlations with age and between TMS measures were assessed by computing Pearson 's product-moment correlation coefficient . We have also looked for correlations between these parameters and gender . Partial and part correlations were employed as appropriate . Significance level was set at P < 0.05 . Results The mean and range of the values for all TMS measures are summarized in the Table 1 . Table 1TMS measures of corticospinal excitability and interhemispheric inhibitionCorticospinal excitabilityLeft hemisphere Right hemisphereMotor thresholds -LRB- % stimulator 's intensity -RRB- Resting -LRB- RMT -RRB- 37.6 -LRB- 28 -- 65 -RRB- 36.4 -LRB- 29 -- 50 -RRB- Active -LRB- AMT -RRB- 28.4 -LRB- 19 -- 45 -RRB- 28 -LRB- 22 -- 39 -RRB- RC of active MEP amplitude -LRB- CMAP corrected -RRB- Mean MEP amplitude recorded 90 % AMT0 .02 -LRB- 0.01 -- 0.06 -RRB- -- 100 % AMT0 .03 -LRB- 0.01 -- 0.07 -RRB- * -- 110 % AMT0 .06 -LRB- 0.02 -- 0.18 -RRB- * -- 120 % AMT0 .09 -LRB- 0.03 -- 0.35 -RRB- * -- 140 % AMT0 .25 -LRB- 0.06 -- 0.51 -RRB- * -- 150 % AMT0 .30 -LRB- 0.10 -- 0.57 -RRB- * -- 160 % AMT0 .34 -LRB- 0.13 -- 0.56 -RRB- * -- 170 % AMT0 .22 -LRB- 0.39 -- 0.62 -RRB- -- Maximum MEP amplitude recorded0 .38 -LRB- 0.13 -- 0.62 -RRB- * -- AUC12 .8 -LRB- 1.8 -- 23.4 -RRB- * -- Parameter estimates -LRB- Boltzman model -RRB- MEPmax/CMAP0 .4 -LRB- 0.13 -- 0.72 -RRB- * -- I50 -LRB- % AMT -RRB- 137 -LRB- 115 -- 168 -RRB- -- 1/slope0 .14 -LRB- 0.05 -- 0.37 -RRB- -- IHI -LRB- targeting the right M1 -RRB- 10 ms40 msrest IHI0 .61 -LRB- 0.32 -- 0.9 -RRB- 0.6 -LRB- 0.28 -- 1.1 -RRB- activeIHI0 .54 -LRB- 0.1 -- 0.89 -RRB- 0.57 -LRB- 0.2 -- 1 -RRB- changeIHI -LRB- activeIHI/restIHI -RRB- 0.96 -LRB- 0.42 -- 2.47 -RRB- 0.97 -LRB- 0.5 -- 1.49 -RRB- * CMAP , compound motor action potential ; AUC , area under the curve ; MEPmax , maximum MEP amplitude estimated ; I50 , stimulation intensity needed to get a response of 50 % of the maximal MEP ; IHI , interhemispheric inhibition ; restIHI , IHI measured with both hands relaxed ; activeIHI , IHI measured during a tonic contraction of the dominant hand at 15 -- 20 % MVC ; changeIHI , values < 1 indicate stronger IHI at the active condition * Significant correlation with advancing age -LRB- P < 0.05 -RRB- Corticospinal excitability Threshold values were not different between the left and right M1 . Age was not correlated with RMT or AMT on either side or the amplitude of the CMAP . The mean amplitude -LRB- CMAP corrected -RRB- of the active MEPs recorded during the construction of the recruitment curves was negatively correlated with age at all stimulation intensities between 100 -- 160 % AMT -LRB- 100 % AMT : r = − 0.431 , P = 0.02 ; 110 % AMT : r = − 0.397 , P = 0.03 ; 120 % AMT : r = − 0.481 , P = 0.007 ; 140 % AMT : r = − 0.556 , P = 0.001 ; 150 % AMT : r = − 0.457 , P = 0.11 ; 160 % AMT : r = − 0.463 , P = 0.01 -RRB- . The same was true for the amplitude of the maximum MEP recorded -LRB- Pearson 's r = − 0.485 , P = 0.007 -RRB- -LRB- Fig. 2a -RRB- . Age was negatively correlated with the total area under the RC -LRB- Pearson 's r = − 0.585 , P = 0.001 -RRB- -LRB- Fig. 2b -RRB- . From the parameters estimated using the Boltzmann model , MEPmax showed a weak correlation with age -LRB- r = − 0.397 , P = 0.04 -RRB- ; age was not correlated with the maximum slope or I50 . Fig. 2Correlations between age and TMS parameters . There was a significant negative correlation between the amplitude of the maximum MEP recorded during the construction of the RC -LRB- a -RRB- and the total area under the RC -LRB- b -RRB- . Age was negatively correlated with changeIHI at 40 ms -LRB- d -RRB- but not at 10 ms -LRB- c -RRB- . CMAP , compound motor action potential , RC , recruitment curve constructed during tonic contraction of the target muscle , IHI , interhemispheric inhibition , restIHI , IHI measured with both hands relaxed , activeIHI , IHI measured during a tonic contraction of the dominant hand at 15 -- 20 % MVC , changeIHI , values < 1 indicate stronger IHI at the active condition Gender was not correlated with any of the TMS measures of corticospinal excitability . Interhemispheric inhibition Most subjects showed some amount of IHI at rest ; only in one subject could restIHI40 not be elicited . Paired-samples t test did not show any difference between restIHI10 and restIHI40 -LRB- P = 0.44 -RRB- . Because the amount of IHI depends on the intensity used for both the conditioning and the test stimulus -LRB- Ferbert et al. 1992 ; Chen et al. 2003 -RRB- we looked for correlations between these values and age . Age was not correlated with the intensities used to stimulate either the left M1 -LRB- 70-mm coil ; 45.7 ± 7.1 for IHI10 and 45.8 ± 7.2 for IHI40 -RRB- or the right M1 -LRB- 50-mm coil ; 46.2 ± 8.6 for IHI10 and 46.9 ± 8.1 for IHI40 -RRB- . The amplitude of the MEPs elicited by the test stimulus and by the conditioning stimulus was slightly higher for the restIHI40 but the values fell within the target range of 1 -- 1.5 mV -LRB- see below -RRB- . During activation of the right hand the MEP elicited by the test stimulus in the resting left FDI tended to increase -LRB- from 1.23 ± 0.53 to 1.44 ± 0.67 for IHI10 and from 1.48 ± 0.58 to 1.64 ± 0.70 for IHI40 -RRB- , but this was not significant across the group , as reported earlier for low-strength isometric contractions -LRB- Liepert et al. 2001 -RRB- . As expected , the amplitude of the MEP elicited by the conditioning pulse in the right FDI increased significantly during activation of the muscle -LRB- from 1.27 ± 0.40 to 5.95 ± 1.69 , P < 0.001 for IHI10 and from 1.5 ± 0.47 to 6.17 ± 2.57 , P < 0.001 for IHI40 -RRB- . There was an overall tendency for stronger IHI during activation of the right FDI at both ISIs , but this did not reach significance . In fact , changeIHI was quite variable ranging from more inhibition to less inhibition compared to the resting condition . Because changeIHI might be biased by the amount of IHI at rest we looked for correlations between changeIHI and restIHI ; there was none for either ISI . There was no correlation between age and changeIHI10 -LRB- Fig. 2c -RRB- . However , we found a significant positive correlation between age and changeIHI40 -LRB- r = 0.444 , P = 0.02 -RRB- -LRB- Fig. 2d -RRB- . In other words , when younger individuals activated their right hand the amount of inhibition targeting the ipsilateral -LRB- right -RRB- motor cortex increased ; with increasing age this phenomenon was gradually attenuated and often reversed . Because age showed a significant correlation with the amplitude of the active MEPs we performed semi-partial correlations correcting for the change seen in the amplitude of the conditioning MEP between the resting and the active condition -LRB- changeMEP = activeMEP/restingMEP -RRB- . Again no correlation was found between age and changeIHI10 ; the correlation between age and changeIHI40 remained and was in fact slightly stronger -LRB- r = 0.553 , P = 0.006 -RRB- . Gender was not significantly correlated with any of the IHI measures ; in line with a previous report -LRB- De Gennaro et al. 2004 -RRB- there was a tendency for a positive correlation between female gender and the amount of restIHI10 targeting the right hemisphere , but this finding did not reach significance in our group of subjects -LRB- r = 345 , P = 0.07 -RRB- . Finally , changeIHI was not correlated with any of the measures of corticospinal excitability elicited from the stimulation of the left M1 . Discussion The purpose of this study was to investigate the effect of age on the interhemispheric balance between the two primary motor cortices and in particular the modulation of inhibition targeting the right M1 during activation of the right hand -LRB- changeIHI -RRB- . We found that the amount of tonic inhibition -LRB- restIHI -RRB- was very variable across the group but age could not explain this variability . However , age was significantly correlated with changeIHI . As reported previously , when young individuals perform a low strength grip , the inhibition targeting the ipsilateral M1 tends to increase -LRB- Ferbert et al. 1992 -RRB- . Our data show that with increasing age this extra inhibition is not as strong and some degree of disinhibition may be present instead . Interestingly , the effect of age was significant for the 40 ms ISI -LRB- changeIHI40 -RRB- but no correlation was found between age and changeIHI10 . Our results on changeIHI are in keeping with the findings from functional imaging studies . A number of studies have consistently shown that task-related activation is less lateralised in older individuals -LRB- for review see Ward 2006 -RRB- . This bilateral recruitment includes primary and non-primary motor areas ; activation of the latter seems to characterise more complex tasks . Regarding the primary motor cortices , reduced deactivation of the M1 ipsilateral to the moving hand has been a common finding among studies using different scanning paradigms -LRB- Hutchinson et al. 2002 ; Ward and Frackowiak 2003 ; Naccarato et al. 2006 ; Ward et al. 2007 -RRB- . It has been hypothesized that this phenomenon could be mediated transcallosally . In support of this hypothesis , we have directly demonstrated that there is task-related reduction in interhemispheric inhibition with advancing age at least when the right hand is activated . The differential effect of age on changeIHI10 and changeIHI40 is an interesting finding that adds to the current knowledge of the cortical circuits that these measures reflect . So far , it is thought that both short latency IHI -LRB- 8 -- 12 ms -RRB- and long latency IHI -LRB- 40 -- 50 ms -RRB- are mediated through excitatory callosal projecting neurons that are distinct from corticospinal neurones -LRB- Lee et al. 2007 -RRB- . In accordance with this view , corticospinal output and IHI measures in this study did not correlate . The callosal neurons are thought to activate inhibitory interneurons in the contralateral M1 -LRB- Daskalakis et al. 2002 ; Chen 2004 -RRB- , but these connections may differ for short and long latency IHI -LRB- Chen et al. 2003 ; Kukaswadia et al. 2005 -RRB- . The neurotransmitters involved are not entirely understood but there is evidence of significant involvement of GABAB-ergic activity . However , Irlbacher et al. -LRB- 2007 -RRB- , have recently demonstrated that exogenous enhancement of GABAB activity strengthens long IHI but has little effect on short IHI at rest . Long IHI was also sensitive to GABAA agonists -LRB- Irlbacher et al. 2007 -RRB- . Finally , Chen et al. -LRB- 2004 -RRB- , has shown that activation of the target muscle results in a reduction in the IHI targeting the active M1 -LRB- the opposite direction than the one studied here -RRB- measured at 8 ms but has little effect on the IHI40 . We have shown that advancing age has an effect on the modulation of IHI during voluntary muscle contraction at 40 ms but not at 10 ms. We have thus provided additional evidence that IHI10 and IHI40 may respond differently to dynamic changes within the motor system and thus may represent physiologically distinct phenomena . This evidence could be strengthened in the future by testing the effect of age on IHI in both directions , i.e. the IHI targeting the motor cortices ipsilateral and contralateral to the moving hand . Why is IHI40 not enhanced during voluntary contraction in older individuals ? One possible explanation is age-related failure of the involved pathways . MRI studies have reported age-related reduced fractional anisotropy within the corpus callosum suggesting callosal fibre degeneration -LRB- for review see Minati et al. 2007 -RRB- . However , for callosal degeneration to be the cause of our finding , one would expect some effect on IHI10 as well . Another possibility is that the inhibitory circuits with which the callosal fibres synapse are less excitable . Previous studies have provided some evidence of age-related reductions in cortical inhibition . For example , GABAA-ergic short-interval intracortical inhibition -LRB- SICI -RRB- assessed with a biphasic stimulator -LRB- Peinemann et al. 2001 -RRB- and cortical reciprocal inhibition -LRB- Hortobagyi et al. 2006 -RRB- are reduced in older individuals . However , Wasserman et al. -LRB- 2002 -RRB- failed to show a correlation between SICI and advancing age in a large series of normal subjects . Others have found increased SICI in middle-aged adults -LRB- Kossev et al. 2002 -RRB- . Further experiments , which include active conditions are needed to study these associations in the aging brain . Finally , it should be noted that although TMS-measured IHI is thought to reflect mainly transcallosal connections , Gerloff et al. -LRB- 1998 -RRB- has demonstrated a role for other pathways involving subcortical and/or spinal structures , the exact nature of which is unclear . Age related changes in these pathways may therefore also contribute to the correlations that we have observed . Another question is whether the age-related reduced activity reported in multiple inhibitory systems , including IHI is an inevitable consequence of neurodegeneration or in fact represents a compensation strategy of the aging brain . Similar changes have been described in response to brain injury and have been interpreted as markers of cortical reorganization -LRB- Ward and Cohen 2004 ; Talelli et al. 2006 -RRB- . The relative preservation of changeIHI10 could suggest that the release from inhibition is not uncontrolled or at least it occurs in a hierarchical manner . For example , IHI10 may be important for direct suppression of mirror activity in the contralateral M1 -LRB- Duque et al. 2005 -RRB- . Longer latency IHI40 , on the other hand , may reflect polysynaptic pathways extending even beyond the primary motor cortices . In that case relatively less inhibition in an active state could allow bilateral recruitment if that was necessary . In this study , there was no correlation between changeIHI40 -LRB- or any other IHI measure -RRB- and any of the measures of corticospinal excitability despite the fact that the latter appeared to be compromised in older individuals . This finding could mean that changeIHI40 does not reflect an adaptation to the failing corticospinal pathways . However , it should be kept in mind that if compensatory mechanisms are indeed operating with increasing age -LRB- or decreasing corticospinal output -RRB- TMS may not measure the real deficit but the compensated deficit . The next reasonable step could be to study a series of elderly individuals known to have different levels of manual dexterity and look for correlations between electrophysiological and behavioural measures , including mirror movements during performance of complex motor tasks . We found variable effects of age on parameters relating to corticospinal excitability . Motor thresholds were not affected in keeping with previous reports -LRB- Wassermann 2002 ; Oliviero et al. 2006 ; Hortobagyi et al. 2006 -RRB- . We have found negative correlations between age and the amplitude of the active MEP at most stimulation intensities , between age and the amplitude of maximum MEP and finally between age and the total area under the recruitment curve -LRB- AUC -RRB- . These results are in agreement with previous findings of reduced amplitude of the MEPs elicited during an isometric contraction -LRB- Oliviero et al. 2006 ; Sale and Semmler 2005 -RRB- . The values derived from the Boltzmann model did not add extra information , since there was no correlation between age and the maximal slope of the curve or the stimulation intensity required to obtain 50 % MEPmax -LRB- I50 -RRB- . Pitcher et al. -LRB- 2003 -RRB- have previously reported that I50 significantly increased with increasing age . In other words , the recruitment of the MEPs was slower at low stimulation intensities . The authors discussed that this finding may reflect reduced excitability or asynchronous activation of spinal motorneurons . In this study we did not perform measures of spinal excitability mainly due to time limitations . We have , however , constructed our RCs during background activation of the target muscle ; that means that some a-motorneurons are already activated and the resulting measures are thus less subject to changes in spinal cord excitability -LRB- Day et al. 1989 -RRB- . We propose that increasing age does have a detrimental effect on the total output of primary motor cortex and that the mechanisms underlying -LRB- or compensating for -RRB- this effect are variable ; thus a summary variable such as the AUC might be more suitable as a surrogate marker of overall corticospinal output . In conclusion , this study has shown for the first time that there is an age-related reduction in the extra inhibition targeting the right hemisphere during an isometric handgrip with the right hand . These changes may underlie the bihemispheric pattern of activation seen in functional imaging studies of older individuals performing a unimanual hand task . Should our findings be confirmed , studies of interhemispheric balance may prove to be a useful marker of reorganization in the aging brain .

O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O

motor system
interhemispheric inhibition
transcranial magnetic stimulation
aging