Doi:10.1016/j.clinph.2004.04.015

Clinical Neurophysiology 115 (2004) 2157–2163 Fluoxetine facilitates use-dependent excitability Burkhard Pleger*, Peter Schwenkreis, Christian Gru¨nberg, Jean-Pierre Malin, Martin Tegenthoff Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Buerkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany Objectives: In poststroke patients, fluoxetine, a selective serotonin-reuptake inhibitor, as an adjunct to physical therapy provided a better functional recovery from motor deficits. The aim of this study was to investigate the effect of a single dose of 20 mg fluoxetine on motorlearning and associated cortical changes in healthy right-handed subjects in order to get deeper insight into its facilitating influence on humanmotor cortex.
Methods: Subjects performed a motor task consisting of a simultaneous co-contraction of the abductor pollicis brevis (APB) and the deltoid muscle with and without fluoxetine in a placebo-controlled double-blinded crossover study design. Immediately before and aftermotor learning motor output maps of the APB muscle were assessed in order to get insight into plastic changes of the musclerepresentation.
Results: We found a significantly improved motor performance under both conditions without having substantial differences between placebo and fluoxetine. After the completion of the motor task there was a medial shift of the APB muscle motor output map. Only afterthe administration of fluoxetine the sum of MEP amplitudes (SOA) increased and the motor output map enlarged.
Conclusions: These findings provide evidence for a use-dependent facilitating effect of fluoxetine on cortical excitability but not on Significance: Our findings are not in line with previous experiments in poststroke patients. However, long-term treatment with fluoxetine may additionally improve motor function by upregulating serotonergic receptors. Further studies investigating the influence oflong-term treatment on cortical excitability and psychophysics may therefore provide deeper insight into a possible therapeuticalefficiency of fluoxetine in poststroke patients.
q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Transcranial magnetic stimulation; Primary motor cortex; Plasticity; Fluoxetine; Serotonin (). Among otherantidepressants, it inhibits 5-HT reuptake selectively, with The application of the endogenous transmitter 5-hydro- no anticholinergic activity and limited side-effects ( xytrytamine (5-HT, serotonin) into cell cultures causes long-term facilitation of sensorimotor synapses due in part an adjunct to physical therapy provided a better functional to growth of new presynaptic varicosities ( recovery from motor deficits (). In first ). In several animal experiments, 5-HT showed the functional magnetic resonance imaging experiments, capacity to modulate purposeful motor responses Pariente et al. found a fluoxetine-dependent hyperactivation in the ipsilesional primary motor cortex giving rise to an enhanced hemodynamic response of the perilesional tissue inhibitor fluoxetine accumulates in the brain relative to the plasma and promotes an amplified serotonin concentration In the present study we investigated the effect of a single dose of 20 mg fluoxetine on psychophysical and * Corresponding author. Tel.: þ 49-234-3026094; fax: þ 49-234- cortical changes in healthy right-handed subjects in order to get deeper insight into its facilitating influence on E-mail address: burkhard.v.pleger@ruhr-uni-bochum.de (B. Pleger).
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2004.04.015 B. Pleger et al. / Clinical Neurophysiology 115 (2004) 2157–2163 human motor system. In previous studies synchronised movement of two limb muscles led to rapid plasticchanges of the motor output map TMS was applied using a figure-of-eight-shaped coil (outside diameter 8.7 cm, peak magnetic field strength the present study subjects performed a so-called 2.2 T, peak electric field strength 660 V/m) that was connected with a Magstim 200 HP device (monopolar contraction of the abductor pollicis brevis (APB) and waveform/The Magstim Company). The TMS measurement was performed immediately before and after the co-con- traction task. The subjects were seated comfortably in a double-blinded crossover study design. In all subjects chair. Motor evoked potentials (MEP) were recorded on an motor output map of the APB muscle was assessed by EMG device (sampling rate: 5000 Hz/Neuropack 8, Nihon transcranial magnetic stimulation (TMS) of the primary Kohden) with surface electrodes from the APB muscle of the dominant hand. The band pass filter was set from 20 Hzto 2 kHz, the gain from 0.1 to 1 mV/D. The sufficientmuscle relaxation during the examination was continuously monitored by EMG (gain 0.1 mV/D). The TMS coil washeld tangentially to the head in an anterior – posterior direction, with the grip pointing backwards. Motor threshold(MT) was defined as the minimum intensity which produced We examined ten healthy right-handed subjects (five men five motor evoked potentials . 50 mV out of ten trials. It was and four women, aged 25 – 29 years, 27.3 ^ 3.3 years, determined over that scalp position were TMS previously mean ^ standard error). They all gave their written elicited the highest amplitude. Stimulation intensity was set informed consent, and the protocol of the study was to 110% of the motor threshold. Starting at the scalp approved by the local ethical committee.
position of the highest amplitudes, the motor cortex was The study was performed in a placebo-controlled examined in dorsal, rostral, lateral and medial direction in double-blinded crossover design. The subjects had to steps of 1 cm until no further MEP could be elicited. For a participate in two sessions. Therefore, the supervisor systematic examination of the primary motor cortex we used (M.T.) randomly divided them into two groups, each a tight fitting cap with a coordinate system on it (1 £ 1 cm consisting of five subjects. The first group started after the width). The coordinate system was arranged relative to Cz, administration of a single dose of 20 mg fluoxetine, whereas which was identified as the intersection of the interaural line the subjects of the second group first received placebo.
ðy-axis), and the connection between nasion and inion In line with previous co-contraction studies ( ðx-axis). Eight stimuli were applied to each position, and the responses (peak-to-peak amplitudes) were averaged. These the groups were reversed after an interval of two averaged amplitudes were considered for further statistical weeks in order to avoid a carry over effect. The investigators analysis. Averaged amplitudes smaller than 10 mV were did not know if the subjects had taken placebo or fluoxetine rejected. Afterwards, we calculated the sum of all prior to each session. The randomization code was kept by MEP-amplitudes of the motor output map (SOA), and its the supervisor and broken at the end of the study after the amplitude-weighted centre of gravity (COG). The centre of individual data analysis had been completed.
gravity (COG) is a single x – y coordinate derived from the Under both conditions, subjects had to perform a motor distribution of MEP amplitudes within the motor output task 6 h after drug intake to guarantee peak plasma area. It was calculated according to the following formula: concentration after fluoxetine administration ( the number of positions from which MEPs could be consisted of a synchronised movement of the abductor elicited was used as a marker for the area size of the pollicis brevis (APB) muscle and the deltoid muscle (for a detailed description see ). The subjectswere instructed to make brisk and short movements of both muscles as synchronously as possible. Over 1 h,three co-contractions per minute had to be performed.
To evaluate differences of the TMS parameters assessed During each single co-contraction we measured the under placebo and fluoxetine we used an ANOVA for latency difference between the onsets of both muscle repeated measurements (pre vs. post training) with the contractions using EMG-monitoring from surface electro- within-subject factor ‘condition’ (placebo vs. fluoxetine).
des. We used the differences between the muscle onsets as For post-hoc analysis we then used the student’s paired a marker of motor performance. After each co-contraction t-test to compare the TMS parameters obtained before and the subjects were informed of the results and encouraged after the task within each session. We also checked the reproducibility of the neurophysiological data B. Pleger et al. / Clinical Neurophysiology 115 (2004) 2157–2163 by comparing the maps obtained prior to motor learning of 12.41 ^ 1 ms; P , 0:001). Using post-hoc t-test, we found significantly reduced time differences between the first To evaluate the effect of repetitive co-contraction on and the successive sessions (1 – 10 vs. 11 – 20: P ¼ 0:003; motor performance, the mean latency differences between 1 – 10 vs. 21 – 30: P ¼ 0:0003; 1–10 vs.31 –40: P ¼ 0:001; the onsets of both muscles for the intervals 0 – 10, 10 – 20, 20 – 30, 30 – 40, 40 – 50 and 50 – 60 min were calculated in P ¼ 0:0004). Using the ANOVA for repeated measure- each subject and for each session. We used an ANOVA ments and the within-subject factor ‘time £ condition’, for repeated measurements and post-hoc t-test analysis we found no differences between placebo and fluoxetine (Bonferroni-corrected for multiple comparisons) to express ðFð5;80Þ ¼ 0:59; P ¼ 0:7; ‘time’: Fð5;80Þ ¼ 39:59; P , 0:001; psychophysical improvement during the motor task As a marker for the reproducibility of the neurophysio- logical data we found no differences in the SOA between Comparing the baseline performance during the first placebo and fluoxetine prior to the motor task (placebo: 10 min we found no significant differences between placebo (31.53 ^ 4 ms, mean ^ standard error) and fluoxetine P ¼ 0:31). Using the ANOVA for repeated measurements condition (29.45 ^ 2.4 ms; paired t-test: P ¼ 0:59).
with the within-subject factor ‘time £ condition’ we found During the course of the task we found a significant significantly increased SOA ðFð1;16Þ ¼ 13:33; P ¼ 0:002; shortening of the latency differences between the onset of post-hoc t-test: pre- vs. post-fluoxetine: P ¼ 0:001; post: the APB and deltoid muscle contraction (ANOVA with 1446 ^ 168 mV, ). Under placebo we found no within-subject factor ‘time’: placebo: Fð1;8Þ ¼ 23:93; changes of the SOA after the completion of the task P ¼ 0:001; fluoxetine: Fð1;8Þ ¼ 49:96; P ¼ 0:0001) indicat- (post: 1379 ^ 127 mV, t-test: P ¼ 0:92).
ing a significant motor performance improvement underboth conditions. In the placebo session, the mean latency during the first 10 min was 31.53 ^ 4 ms, and during the last We found no differences in the COG between placebo 10 min 12.38 ^ 1.1 ms (t-test: P ¼ 0:001). The Bonferroni- and fluoxetine prior to the motor task using paired t-test (x-coordinate: P ¼ 0:25; y-coordinate: P ¼ 0:51; differences between the first and the successive 10 min In the placebo session, we found a significant medial shift of (1 – 10 vs. 11 – 20: P ¼ 0:2). Afterwards subjects showed the y-coordinate of the COG after the completion of the increasingly reduced time differences between the onsets of motor task (pre: 2 4.66 ^ 0.26 cm, post: 2 4.54 ^ 0.26 cm, both muscles in the following periods that all reached t-test: P , 0:001). We also found a significant medial shift significant level (1 – 10 vs. 21 – 30: P ¼ 0:03; 1 – 10 vs.31 – 40: P ¼ 0:04; 1–10 vs. 41–50: P ¼ 0:01; 1–10 vs.
2 4.59 ^ 0.23 cm, t-test: P , 0:001; ANOVA, within-sub- 51 – 60: P ¼ 0:009). In the fluoxetine session we also found ject factor ‘time £ condition’: Fð1;16Þ ¼ 24:95; P ¼ 0:0001).
significantly reduced latencies (from 29.45 ^ 2.4 ms to Contrarily, we found no significant differences for Fig. 1. A: Shown is the motor improvement during each session of the co-contraction task. Shown are the results obtained under placebo and fluoxetinecondition. The whiskers represent the standard error.
Table 1Sown are the individual SOA (mV), the y- (refers to the lateral-to-medial axis) and x-coordinate (refers to the posterior-to-anterior axis) of the COG (cm) and the size of the area (cm2) elicited by TMS underplacebo and fluoxetine condition ‘time £ condition’Within-subject factor Below we show group data (mean, standard error) as well as the results of statistical analysis (ANOVA for repeated measurements, post-hoc t-test).
B. Pleger et al. / Clinical Neurophysiology 115 (2004) 2157–2163 the x-coordinate of the COG (placebo: pre: 2 0.17 ^ post-session, we found equal motor thresholds (placebo: 0.19 cm, post: 2 0.09 ^ 0.21 cm; fluoxetine: pre: 2 0.34 ^ 41.6 ^ 1.9%, fluoxetine: 43.3 ^ 1.1%).
0.25 cm, post: 2 0.31 ^ 0.24 cm; ANOVA, within-subjectfactor ‘time £ condition’: Fð1;16Þ ¼ 0:52; P ¼ 0:47Þ: In the present study we investigated the influence of the Before the motor task we found non-significant selective 5-HT reuptake inhibitor fluoxetine on use-depen- differences in the size of the area between placebo and dent plastic changes in human primary motor cortex.
fluoxetine that was also indicative for the reproducibility of Healthy right-handed subjects performed a motor task the motor maps (placebo: 10.7 ^ 0.78 cm2, fluoxetine: consisting of a co-contraction of two limb muscles.
10.5 ^ 0.57 cm2, t-test: P ¼ 0:84; Afterwards This paradigm has been proved to be an appropriate motor maps significantly enlarged (ANOVA, within-subject model to study the pharmacological modulation of train- Under placebo we found a tendentious enlargement of the motor map after the motor task (post: 11.1 ^ 0.74 cm2, repetitive co-contraction resulted in progressively shortened t-test pre vs. post: P ¼ 0:08). Under fluoxetine the time intervals between the onsets of both muscles ( enlargement of the motor map, however, reached significant level (post: 12.1 ^ 0.81 cm2, t-test pre vs. post: P ¼ 0:008).
) without significant differences between both The shows the results of the MEP mapping performed conditions. This lack of pharmacological effects on immediately before and after the completion of the motor psychophysical level was surprising as Pariente et al.
task under both conditions in one single-subject and the previously reported a significantly improved finger changes in motor performance during the course of the task.
tapping rate and grip force of the hemiparetic side inpost-stroke patients under a single dose of fluoxetine We found no differences in the MT between placebo and However, our findings are in line with previous studies fluoxetine prior to the motor task ðP ¼ 0:31Þ: In the pre and that also failed to show pharmacological influences on Fig. 2. Single-subject co-contraction effect: shown are the results of the TMS mapping performed before and after the completion of the motor task under bothconditions (placebo: above; fluoxetine: below). The graphs between both motor maps show the changes in motor performance during the course of the task(placebo: from 24.9 ^ 2.3 (mean values ^ standard error) to 13.8 ^ 1.2 ms, paired t-test 0 – 10 vs. 51 – 60 min P , 0:001; fluoxetine: from 27.5 ^ 2 to15.8 ^ 1 ms; P , 0:001). Note the differences of changes in motor maps between placebo (above) and fluoxetine condition (below), especially theenlargement of the area and the gain in SOAs.
B. Pleger et al. / Clinical Neurophysiology 115 (2004) 2157–2163 fluoxetine seem therefore to have complex influences on One hour of co-contraction resulted in significantly different parameters of cortical excitability.
shortened time intervals between the onsets of the APB In summary, our findings provide evidence for a and the deltoid muscle, which was not affected by the use-dependent facilitating effect of fluoxetine on human administration of amphetamine. Motor improvement, motor cortex excitability. However, we found no gain in however, resulted in a significant medial shift of the APB motor performance after a single dose of fluoxetine.
output map. Consequently, the co-contraction task may be Long-term treatment may additionally improve motor considered as an appropriate task to investigate facilitating influences on re-organizational changes of human primary motor cortex. But it seems not appropriate to study parallel effects on behavioral level. In line with previous studies, gating the influence of long-term treatment with selective we also found a medial shift of the APB motor output map 5-HT reuptake inhibitors as an adjunct to physical therapy under both conditions. This shift was orientated towards the may therefore provide deeper insight into their possible representation of the deltoid muscle. Therefore it might therapeutical efficiency in post-stroke patients.
be indicative of a change in the underlying corticalrepresentation ().
Synchronised neuronal activity that parallels cortical reorganization can be referred to a principle presented byHebb (He suggested This study was supported by a grant from the that individual neurons could participate in different cell Ruhr-University Bochum (FORUM F 291/01) and by a assemblies and be involved in multiple functions and grant from the Scientific Research Council of BG-Kliniken representations (Long-term potentiation (LTP) Bergmannsheil, Bochum (to P.S.). We thank Mr Steve of motor synapses can be induced in Hebbian fashion Langan for skilful editing of the manuscript.
by pairing weak presynaptic stimulation with strongpost-synaptic depolarization (for a review see This mechanism can also function only at proximal synapses, suggesting that dendritic spikes participategenerally in a form of synaptic potentiation that does not Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of require post-synaptic action potential firing in the axon fluoxetine. Clin Pharmacokinet 1994;26:201 – 14.
Barbeau H, Rossignol S. Initiation and modulation of the locomotor pattern representation, which are suggested by our results might in the adult chronic spinal cat by noradrenergic, serotonergic and therefore depend on the synchronicity of the co-contraction dopaminergic drugs. Brain Res 1991;546:250 – 60.
Bieger D. Role of bulbar serotonergic neurotransmission in the movement. This in turn might induce LTP-like processes initiation of swallowing in the rat. Neuropharmacology 1981;20: that promote re-organizational changes of the participating Cazalets JR, Sqalli-Houssaini Y, Clarac F. Activation of the central pattern Several animal experiments showed purposeful motor generators for locomotion by serotonin and excitatory amino acids in responses due to the application of 5-HT ( neonatal rat. J Physiol 1992;455:187– 204.
Chen Y, Peng L, Zhang X, Stolzenburg JU, Hertz L. Further evidence that fluoxetine interacts with a 5-HT2C receptor in glial cells. Brain Res neurons were activated in association with increased muscle motor activity, especially if the motor activity is in the Cohen LG, Gerloff C, Ikoma K, Hallett M. Plasticity of motor cortex repetitive or central pattern generator mode ( elicited by training of synchronous movements of hand and shoulder.
Thus, serotonergic neurons seem to promote motor output if it is generated in Hebbian fashion.
Dam M, Tonin P, De Boni A, Pizzolato G, Casson S, Ermani M, Freo U, Piron L, Battistin L. Effects of fluoxetine and maprotiline on functional The present findings corroborate the hypothesis of a recovery in post-stroke hemiplegic patients undergoing rehabilitation reorganization processes of the APB representation. Using Dinse HR, Ragert P, Pleger B, Schwenkreis P, Tegenthoff M. Pharmaco- TMS, Ilic et al. previously investigated the effects of the logical modulation of perceptual learning and associated cortical selective 5-HT reuptake inhibitor sertaline on human motor reorganization. Science 2003;301:91– 4.
Glanzman DL. Post-synaptic regulation of the development and long-term cortex excitability in healthy subjects ( plasticity of Aplysia sensorimotor synapses in cell culture. J Neurobiol Under the influence of sertaline, they found a steeper intensity curve suggesting an increased excitability of the Golding NL, Staff NP, Spruston N. Dendritic spikes as a mechanism for cortico-spinal neurone. In the present study, under cooperative long-term potentiation. Nature 2002;418:326 – 31.
the influence of fluoxetine the repetitive co-contraction of Gram L, Fluoxetine . Engl J Med 1994;331:1354 – 61.
Hebb DO. The organization of behaviour. New York: Wiley; 1949.
the APB and the deltoid muscle resulted in an increase of Hrdina PD, Vu TB. Chronic fluoxetine treatment upregulates 5-HT uptake the SOA and an enlargement of the APB representation.
sites and 5-HT2 receptors in rat brain: an autoradiographic study.
Selective 5-HT reuptake inhibitors like sertaline and B. Pleger et al. / Clinical Neurophysiology 115 (2004) 2157–2163 Ilic TV, Korchounov A, Ziemann U. Complex modulation of human motor Pleger B, Schwenkreis P, Dinse HR, Ragert P, Hoffken O, Malin J-P, cortex excitability by the specific serotonin re-uptake inhibitor sertra- Tegenthoff M. Pharmacological suppression of plastic changes in line. Neurosci Lett 2002;319:116 – 20.
human primary somatosensory cortex after motor learning. Exp Brain Jacobs BL, Fornal CA. Activity of serotonergic neurons in behaving animals. Neuropsychopharmacology 1999;21:9S – 15S.
Pleger B, Fo¨rster A-F, Ragert P, Dinse HR, Schwenkreis P, Malin J-P, Karson CN, Newton JE, Livingston R, Jolly JB, Cooper TB, Sprigg J, Nicolas V, Tegenthoff M. Functional imaging of perceptual learning in Komoroski RA. Human brain fluoxetine concentrations. J Neuropsych human primary and secondary somatosensory cortex. Neuron 2003b; Liepert J, Terborg C, Weiller C. Motor plasticity induced by Schwenkreis P, Pleger B, Ho¨ffken O, Malin J, Tegenthoff M. Repetitive synchronized thumb and foot movements. Exp Brain Res 1999;125: training of a synchronised movement induces short-term plastic changes in the human primary somatosensory cortex. Neurosci Lett2001;312:99– 102.
Mangan PS, Cometa AK, Friesen WO. Modulation of swimming behavior Sommi RW, Crismon ML, Bowden CL. Fluoxetine: a serotonin-specific, in the medicinal leech. IV. Serotonin-induced alteration of synaptic second-generation antidepressant. Pharmacotherapy 1987;7:1 – 15.
interactions between neurons of the swim circuit. J Comp Physiol [A] Tegenthoff M, Witscher K, Schwenkreis P, Liepert J. Pharmacological modulation of training-induced plastic changes in human motor Palvimaki EP, Laakso A, Kuoppamaki M, Syvalahti E, Hietala J. Up- cortex. Electroencephalogr Clin Neurophysiol Suppl 1999;51: regulation of beta 1-adrenergic receptors in rat brain after chronic citalopram and fluoxetine treatments. Psychopharmacology (Berl) Tegenthoff M, Cornelius B, Pleger B, Malin J-P, Schwenkreis P.
Amphetamine enhances training-induced motor cortex plasticity. Acta Pariente J, Loubinoux I, Carel C, Albucher JF, Leger A, Manelfe C, Rascol O, Chollet F. Fluoxetine modulates motor performance and cerebral Yamazaki J, Fukuda H, Nagao T, Ono H. 5-HT2/5-HT1C receptor- activation of patients recovering from stroke. Ann Neurol 2001;50: mediated facilitatory action on unit activity of ventral horn cells in rat spinal cord slices. Eur J Pharmacol 1992;220:237 – 42.

Source: http://homepage.ruhr-uni-bochum.de/burkhard.v.pleger/publications/Pleger_ClinNeurophysiol_2004.pdf