912
Letters to the Editor / Brain Stimulation 7 (2014) 909e921
Ethical standard The authors declare that they acted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All patients included in this survey signed a written informed consent before surgery. Acknowledgment We acknowledge the contributions of the Neurosurgery and Neurology Units staff of San Giovanni Battista Hospital, Turin. Financial disclosures and conflict of interest: Dr. Maurizio Zibetti and Prof. Michele Lanotte received travel grants for attending scientific congresses from Medtronic. Prof. Lopiano Leonardo has received honoraria for lecturing from Medtronic. Dr. Alberto Romagnolo and Dr. Mario Giorgio Rizzone declare no conflict of interests.
Maurizio Zibetti Alberto Romagnolo Emanuela Crobeddu Riccardo Fornaro Aristide Merola Mario Giorgio Rizzone Leonardo Lopiano Michele Lanotte* Department of Neuroscience, University of Torino, Via Cherasco 15, Torino 10126, Italy * Corresponding author. Tel./fax: þ39 011 6334243. E-mail address: [email protected] (M. Lanotte)
Received 12 July 2014 Available online 27 October 2014 http://dx.doi.org/10.1016/j.brs.2014.09.008
References [1] Zrinzo L, Foltynie T, Limousin P, Hariz MI. Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review. J Neurosurg 2012;116:84e94. [2] Fenoy AJ, Simpson Jr RK. Risks of common complications in deep brain stimulation surgery: management and avoidance. J Neurosurg 2014;120:132e9. [3] Xiaowu H, Xiufeng J, Xiaoping Z, et al. Risks of intracranial hemorrhage in patients with Parkinson’s disease receiving deep brain stimulation and ablation. Parkinsonism Relat Disord 2010;16:96e100. [4] Gorgulho A, De Salles AA, Frighetto L, Behnke E. Incidence of hemorrhage associated with electrophysiological studies performed using macroelectrodes and microelectrodes in functional neurosurgery. J Neurosurg 2005;102:888e96. [5] Lanotte MM, Rizzone M, Bergamasco B, Faccani G, Melcarne A, Lopiano L. Deep brain stimulation of the subthalamic nucleus: anatomical, neurophysiological, and outcome correlations with the effects of stimulation. J Neurol Neurosurg Psychiatry 2002;72:53e8. [6] Schaltenbrand G, Wahren W. Atlas for stereotaxy of the human brain. Stuttgart, New York: Thieme Publishers; 1977.
Normalizing Biased Spatial Attention With Parietal rTMS in a Patient With Focal Hand Dystonia Dear Editor, We report the following case to highlight the possible relevance of biased spatial attention in focal hand dystonia (FHD). Deficient sensorimotor inhibition is a prominent pathophysiological feature
of FHD [1,2]. Low-frequency repetitive Trascranial Magnetic Stimulation (rTMS) over contralateral premotor cortex (PMC) can reinforce cortical inhibition and improve motor performance and dystonic symptoms in some patients [3,4]. Here we report the case of a 41year-old right-handed man (23 years of education) with severe task-dependent FHD, affecting the right hand index and middle fingers. FHD had started five years before presentation and was initially associated with an increased use of the computer mouse. At the time of the study, he could not hold the pen correctly during handwriting nor perform any fine hand movement. He also presented with tremors at rest, overflow, and mirror dystonia [2]. The patient attributed a significant part of his motor problems to inability to ‘disengage his thoughts’ from the dystonic hand. He stated that he performed better with the affected hand, when he managed to not ‘think about it.’ The patient’s observations prompted us to explore the possibility that hyper-attention toward the side of the affected hand might play a role in his disorder. We first tested whether the patient would show a rightward bias in visuospatial attention. Then we investigated whether suppression of left posterior parietal cortex (PPC) through inhibitory rTMS could attenuate the attentional bias and hereby alleviate dystonic symptoms. Indeed, inhibitory rTMS over left PPC improves attentional deficits in post-stroke patients presenting with biased spatial attention [5e7]. Attentional bias was assessed by asking the patient to mark the middle of ten 18 cm long horizontal lines. Handwriting was evaluated on signature and a 4 words copying task. He rated perceived symptom change on handwriting, with respect to the most recent evaluation, on a 7 points Lickert scale (3 ¼ significant worsening, 0 ¼ no change, 3 ¼ significant improvement). The patient was also asked to show how to use a stapler (Task 1), toothbrush (Task 2), a cup (Task 3) and a bottle (Task 4). Handwriting and object use were video-taped and offline evaluated on a 10 points scale (0 ¼ unable to perform the task, 10 ¼ normal performance) by an experimenter blind to the condition. The patient also performed a Finger Tapping Task (FTT) with the right and then left hand. He had to press two contiguous keys of the computer key-board with his index and middle finger in alternating order, as quickly and accurately as possible for 30 s. Mirror dystonia was assessed by videotaping the right hand during FTT with the left hand and offline evaluated on a 5 points scale (0 ¼ no dystonia; 5 ¼ maximal dystonia) by an experimenter blind to the condition. Three sessions of 1 Hz rTMS (600 stimuli per session) were applied at 90% of resting motor threshold [8] over left PPC every other day, using a 70 mm figure-of-eight coil and the MagStim Super Rapid stimulator (Magstim Company Ltd., Whitland, UK). A single-pulse TMS hunting procedure, using a PC-based linelength estimation task [9], was employed to functionally localize the PPC site. A nine points grid (3 3 cm) was centered over P3 and 10 stimuli were delivered at each location. The spot where TMS reversed the rightward bias in the majority of trials was found to be 1 cm anterior to P3. Clinical and behavioral evaluation was performed one week before intervention (pre 1), before rTMS on Day 1 (pre 2), after rTMS on Day 3 (post), and one week after intervention (follow-up, FU). A reduced protocol was used for pre and poststimulation evaluation on Day 2 and pre-stimulation evaluation on Day 3. It did not include line bisection and object use and the patient had to copy only two words. The patient signed a written informed consent to participate to the study, which was approved by the Local Ethical Committee. He was free from medications. Results are reported in Table 1. The rightward bisection bias was abolished after PPC stimulation as indexed by significant differences (Wilcoxon test with Bonferroni correction, P ¼ 0.05) between pre 1 and post (P ¼ 0.007), pre 2 and post (P ¼ 0.005), and pre 1 and FU (P ¼ 0.008) conditions. For handwriting, the patient received the highest performance score at baseline of Day 3 that was partly maintained at FU. On the Lickert scale, the patient did not appreciate
586 599 682 493 e (1.55) (2.01)
þ2.85 þ1.65 e 0.05 þ0.40 Pre 1 Day 1 Day 2 Day 3 FU
Results for line bisection (LB), Lickert self-evaluation scale (sign. worsening ¼ significant worsening, sign. improvement ¼ significant improvement), handwriting, use of objects (Task 1 ¼ stapler, Task 2 ¼ toothbrush, Task 3 ¼ cup of coffee, Task 4 ¼ bottle of water), and mirror dystonia (no dyst. ¼ no dystonia; max dyst. ¼ maximal dystonia). Values of left (LH) and right (RH) hemisphere resting motor threshold (RMT) are also reported. LB: mean bisection bias (mm) and relative standard deviation are reported for each experimental condition; positive values indicate rightward bisection bias and negative values leftward bisection bias. Pre ¼ pre-rTMS evaluation; Post ¼ post-rTMS evaluation; Pre 1 ¼ 1-week pre-intervention evaluation; Day 1 ¼ first day of rTMS application, Day 2 ¼ second day of application, Day 3 ¼ third day of application; FU ¼ 1-week follow-up evaluation.
RH LH
32% 32% 31% 32% 31%
Post Pre
e e 2 2 2 3 3 3 1 e 2 1 e 3 3 e e 6 7 6
2 3 e 5 3 Pre
4 5 3 7 e e e 6 7 7
Post Pre
5 5 3 8 e e e þ1 þ1 0.5
Post Pre
Signature
(1.83) (0.82)
e þ2 1 0 e
Post
Task 2 Word copy
Task 1
5 5 e 4 6
Task 3
4 5 e 3 6
Task 4
Pre
Post
(434) (376) (460) (308)
e e 514 (312) 425 (305) 615 (422)
RMT FTT (right hand RT) Mirror dystonia (0 ¼ no dyst., 5 ¼ max dyst.) Use of object (0 ¼ unable to perform, 10 ¼ normal performance) Handwriting (0 ¼ unable to perform, 10 ¼ normal performance)
Lickert scale (3 ¼ sign. worsening, þ3 ¼ sign. improvement) LB
Table 1 Clinical and behavioral evaluation and resting motor threshold.
42% 43% e 43% 43%
Letters to the Editor / Brain Stimulation 7 (2014) 909e921
913
this improvement, while reporting enhanced performance from pre 1 to pre 2, when no objective change in writing performance was observed. Regarding object use, he showed higher scores at postintervention on Tasks 1 and 2 relative to pre-treatment levels. Consistent with handwriting, mirror dystonia was scored lowest at baseline of Day 3. On the FTT, Reaction Times of the dystonic hand were (P < 0.0001) faster (Wilcoxon with Bonferroni correction) for post-stimulation of Day 3 than baseline of Day 1 conditions. Discussion Focal 1 Hz rTMS of left PPC abolished the patient’s rightward attentional bias, in line with studies in post-stroke patients [5,6]. Normalization of attentional bias was associated with improvement of dystonic symptoms, suggesting that hyper-attention toward the side of the dystonic hand contributed to the patient’s FHD. Given the tight link between PPC and PMC during intentional movement, it is likely that maladaptive plasticity, during the use of the dystonic hand, does not spare the PPC, leading to pathological increase of contralateral attention. Thus, PPC may represent a remote target site for stimulation to restore not only biased attention but also deficient premotor inhibition that has been implicated in the pathophysiology of FHD. Indeed, single-pulse TMS over PPC decreases the activity of parieto-frontal areas during modulation of visuospatial attention [9]. Lastly, the discrepancy between self-evaluation scores and handwriting performance highlights the importance of a possible dissociation between the objective reduction in FHD and subjective awareness of symptom amelioration in rTMS studies investigating patients with altered activity of premotor areas, underlying motor awareness [10]. The presence of biased spatial attention might offer a rationale for rTMS treatment over PPC in FHD. The role of attentional bias in FHD and the potential of rTMS over contralateral PPC or other interventions apt to rehabilitate attention warrant further investigation in prospective placebocontrolled trials. Competing interests: The authors report no conflicts of interest. The study was supported by a PRIN (prot. 2010ENPRYE_003) grant.
Raffaella Ricci* Department of Psychology, University of Turin, Italy Neuroscience Institute of Turin (NIT), University of Turin, Italy Adriana Salatino Department of Psychology, University of Turin, Italy Hartwig R. Siebner Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark Gaetano Mazzeo Department of Psychology, University of Turin, Italy Marcello Nobili Unit of Neurology, Koelliker Hospital, Turin, Italy * Corresponding
author. Department of Psychology, University of Turin, Via Po, 14 10123 Torino, Italy. Tel.: þ39 011 6703063. E-mail address: [email protected] Received 20 June 2014 Available online 30 August 2014
http://dx.doi.org/10.1016/j.brs.2014.07.038
914
Letters to the Editor / Brain Stimulation 7 (2014) 909e921
References [1] Siebner HR, Auer C, Conrad B. Abnormal increase in the corticomotor output to the affected hand during repetitive transcranial magnetic stimulation of the primary motor cortex in patients with writer’s cramp. Neurosci Lett 1999;262:133e6. [2] Hallett M. Neurophysiology of dystonia: the role of inhibition. Neurobiol Dis 2011;42:177e84. [3] Borich MR, Arora S, Kimberley TJ. Lasting effects of repeated rTMS application in focal hand dystonia. Restor Neurol Neurosci 2009;27:55e65. [4] Kimberley TJ, Borich MR, Arora S, et al. Multiple sessions of low-frequency repetitive transcranial magnetic stimulation in focal hand dystonia: clinical and physiological effects. Restor Neurol Neurosci 2013;31:533e42. [5] Brighina F, Bisiach E, Oliveri M, et al. 1 Hz repetitive transcranial magnetic stimulation of the unaffected hemisphere ameliorates contralesional visuospatial neglect in humans. Neurosci Lett 2003;336:131e3. [6] Salatino A, Berra E, Troni W, et al. Behavioral and neuroplastic effects of lowfrequency rTMS of the unaffected hemisphere in a chronic stroke patient: a concomitant TMS and fMRI study. Neurocase 2014 Dec;20(6):615e26. [7] Chatterjee A, Ricci R, Calhoun J. Weighing the evidence for cross over in neglect. Neuropsychologia 2000;38:1390e7. [8] Groppa S, Oliviero A, Eisen A, et al. A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2012; 123:858e82. [9] Ricci R, Salatino A, Li X, et al. Imaging the neural mechanisms of TMS neglectlike bias in healthy volunteers with the interleaved TMS/fMRI technique: preliminary evidence. Front Hum Neurosci 2012;6:326. http://dx.doi.org/10. 3389/fnhum.2012.00326. [10] Salatino A, Momo E, Nobili M, et al. Awareness of symptoms amelioration following low-frequency repetitive transcranial magnetic stimulation in a patient with Tourette syndrome and comorbid obsessive-compulsive disorder. Brain Stimul 2014;7:341e3 [Letter].
Long Term Effects of Low Frequency (10 Hz) Vagus Nerve Stimulation on EEG and Heart Rate Variability in Crohn’s Disease: A Case Report Dear Editor, We report the first clinical case of long-term low frequency vagus nerve stimulation (VNS) in a patient with Crohn’s disease (CD), a chronic inflammatory disorder characterized by relapsing and remitting periods of gastrointestinal inflammation [1]. There is no definitive cure of CD and there is a strong need for an efficient treatment inducing sustained remission. We have shown, in an experimental model of CD, that chronic low frequency VNS activates the cholinergic anti-inflammatory pathway through vagal efferents [2]. VNS is thus a therapeutic option for CD though it has only been used at high frequency in epilepsy and depression [3]. Long-term low frequency (10 Hz) VNS has never been tested in CD and its central effect remains unknown. Here, we share our first evaluation of the effect of 10 Hz VNS in CD on both brain and parasympathetic nervous system. Methods A 49 year old male adult with ileal CD since 28 years with ileocecal resection in 1986, under maintenance treatment with immunosuppressant (IMURELÒ: 200 mg/day) since 2005, was implanted with VNS in April 2012 while he was in moderate to severe flare of its CD [Crohn’s disease activity index (CDAI) of 330 (threshold ¼ 150) and ulcerated stenosis of the ileo-colonic anastomosis]. After a written informed consent, the medical team opted for a VNS protocol (http://clinical trial.gov identifier NCT01569503). Under general anesthesia, an electrode (Model 302, Cyberonics, Houston, Texas) was positioned on the left cervical VN and linked to
a stimulator (Model 102). The device was switched on at 0.5 mA the day of the surgery and increased by 0.25 mA each week until 1 mA. Stimulation parameters were: 30 s ON e 5 min OFF, 500 ms, 10 Hz. VNS was continuously performed over 12 months. EEG and electrocardiographic (ECG) recordings were performed one week before, at week 6 and months 6, 9 and 12 post VNS implantation. EEG was recorded from 96 active electrodes (Acticap, Brain products, Germany). Signals were acquired at resting state, eyes-closed, during a 20 min period and digitized at a sampling rate of 500 Hz. Data were further processed off-line using EEG Lab (sccn.ucsd.edu/eeglab) and SPM (www.fil.ion.ucl.ac.uk/spm) toolboxes. Blinks, muscular activity and VNS artifacts were removed using independent component analysis as proposed in EEG Lab. Data were re-referenced to the common average and EEG power was computed in the canonical frequency bands (delta 1e4 Hz; theta 3.5e7 Hz; alpha 7.5e13 Hz; beta 14e29 Hz; gamma 30e45 Hz) using a sliding time window of 10 s duration shifted every 5 s during the whole EEG session. For each frequency band, a Student t-test was performed to test the difference of EEG power between VNS treatment and pre-VNS period. VN activity was explored using heart rate variability (HRV) analysis from ECG recorded signal (Kubios, Finland) as we previously described [4]. A standard spectral analysis was applied on interbeat intervals using a Fast Fourier Transform. High Frequency power spectrum (HF, from 0.15 to 0.40 Hz) component was chosen to characterize parasympathetic tone fluctuations associated to VNS. Results VNS induced significant (P < 0.05) changes in resting EEG in all frequency bands with shared spatial pattern (Fig. 1). In particular, activations were observed over the mediofrontal electrodes for both low and high frequency bands with the most important activation for theta band. An additional activation was found in the occipital electrodes for the gamma band (Fig. 1A). Significant correlations (P < 0.05) were detected between EEG and HF-HRV for delta (T ¼ 3.32), theta (T ¼ 3.26), beta (T ¼ 2.75), and gamma (T ¼ 3.26) frequency bands. Interestingly, a positive correlation was observed between HF-HRV and beta-gamma bands in occipital electrodes. The highest level of significance was in the gamma band for the negative correlation between HF-HRV and EEG power on the left and right temporo-parietal electrodes (Fig. 1B). Beside these effects, the patient presented a significant clinical improvement, with a progressive decrease of the CDAI score and an endoscopic remission at month 12, associated to an increase of the parasympathetic tone as marked by the elevation of HF-HRV (Supplemental Data). Discussion To our knowledge, this is the first time that a positive effect of long-term low frequency VNS is described on EEG, HF-HRV and clinical level in a CD patient. Although we cannot completely rule out a placebo effect or even an improvement unrelated to the treatment, it is worth mentioning that the patient is still in remission after 27 months under VNS and stopping immunosuppressant at month 16. Further, we show that low frequency VNS, supposed to activate efferent fibers, also has an effect on the central nervous system as we have previously shown in rats [5]. We observed significant changes on EEG in both anterior and posterior electrodes. On anterior electrodes, the most important increase was observed in the theta band in fronto-medial electrodes. Kubota et al. [6] reported that frontal midline theta rhythm reflected high level of attentional load and was associated with an increase in both sympathetic and parasympathetic indices. Asada et al. [7] have shown that the anterior cingulate cortex (ACC) is the source of this frontal midline theta rhythm.
Letters to the Editor / Brain Stimulation 7 (2014) 909e921
Ethical standard The authors declare that they acted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All patients included in this survey signed a written informed consent before surgery. Acknowledgment We acknowledge the contributions of the Neurosurgery and Neurology Units staff of San Giovanni Battista Hospital, Turin. Financial disclosures and conflict of interest: Dr. Maurizio Zibetti and Prof. Michele Lanotte received travel grants for attending scientific congresses from Medtronic. Prof. Lopiano Leonardo has received honoraria for lecturing from Medtronic. Dr. Alberto Romagnolo and Dr. Mario Giorgio Rizzone declare no conflict of interests.
Maurizio Zibetti Alberto Romagnolo Emanuela Crobeddu Riccardo Fornaro Aristide Merola Mario Giorgio Rizzone Leonardo Lopiano Michele Lanotte* Department of Neuroscience, University of Torino, Via Cherasco 15, Torino 10126, Italy * Corresponding author. Tel./fax: þ39 011 6334243. E-mail address: [email protected] (M. Lanotte)
Received 12 July 2014 Available online 27 October 2014 http://dx.doi.org/10.1016/j.brs.2014.09.008
References [1] Zrinzo L, Foltynie T, Limousin P, Hariz MI. Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review. J Neurosurg 2012;116:84e94. [2] Fenoy AJ, Simpson Jr RK. Risks of common complications in deep brain stimulation surgery: management and avoidance. J Neurosurg 2014;120:132e9. [3] Xiaowu H, Xiufeng J, Xiaoping Z, et al. Risks of intracranial hemorrhage in patients with Parkinson’s disease receiving deep brain stimulation and ablation. Parkinsonism Relat Disord 2010;16:96e100. [4] Gorgulho A, De Salles AA, Frighetto L, Behnke E. Incidence of hemorrhage associated with electrophysiological studies performed using macroelectrodes and microelectrodes in functional neurosurgery. J Neurosurg 2005;102:888e96. [5] Lanotte MM, Rizzone M, Bergamasco B, Faccani G, Melcarne A, Lopiano L. Deep brain stimulation of the subthalamic nucleus: anatomical, neurophysiological, and outcome correlations with the effects of stimulation. J Neurol Neurosurg Psychiatry 2002;72:53e8. [6] Schaltenbrand G, Wahren W. Atlas for stereotaxy of the human brain. Stuttgart, New York: Thieme Publishers; 1977.
Normalizing Biased Spatial Attention With Parietal rTMS in a Patient With Focal Hand Dystonia Dear Editor, We report the following case to highlight the possible relevance of biased spatial attention in focal hand dystonia (FHD). Deficient sensorimotor inhibition is a prominent pathophysiological feature
of FHD [1,2]. Low-frequency repetitive Trascranial Magnetic Stimulation (rTMS) over contralateral premotor cortex (PMC) can reinforce cortical inhibition and improve motor performance and dystonic symptoms in some patients [3,4]. Here we report the case of a 41year-old right-handed man (23 years of education) with severe task-dependent FHD, affecting the right hand index and middle fingers. FHD had started five years before presentation and was initially associated with an increased use of the computer mouse. At the time of the study, he could not hold the pen correctly during handwriting nor perform any fine hand movement. He also presented with tremors at rest, overflow, and mirror dystonia [2]. The patient attributed a significant part of his motor problems to inability to ‘disengage his thoughts’ from the dystonic hand. He stated that he performed better with the affected hand, when he managed to not ‘think about it.’ The patient’s observations prompted us to explore the possibility that hyper-attention toward the side of the affected hand might play a role in his disorder. We first tested whether the patient would show a rightward bias in visuospatial attention. Then we investigated whether suppression of left posterior parietal cortex (PPC) through inhibitory rTMS could attenuate the attentional bias and hereby alleviate dystonic symptoms. Indeed, inhibitory rTMS over left PPC improves attentional deficits in post-stroke patients presenting with biased spatial attention [5e7]. Attentional bias was assessed by asking the patient to mark the middle of ten 18 cm long horizontal lines. Handwriting was evaluated on signature and a 4 words copying task. He rated perceived symptom change on handwriting, with respect to the most recent evaluation, on a 7 points Lickert scale (3 ¼ significant worsening, 0 ¼ no change, 3 ¼ significant improvement). The patient was also asked to show how to use a stapler (Task 1), toothbrush (Task 2), a cup (Task 3) and a bottle (Task 4). Handwriting and object use were video-taped and offline evaluated on a 10 points scale (0 ¼ unable to perform the task, 10 ¼ normal performance) by an experimenter blind to the condition. The patient also performed a Finger Tapping Task (FTT) with the right and then left hand. He had to press two contiguous keys of the computer key-board with his index and middle finger in alternating order, as quickly and accurately as possible for 30 s. Mirror dystonia was assessed by videotaping the right hand during FTT with the left hand and offline evaluated on a 5 points scale (0 ¼ no dystonia; 5 ¼ maximal dystonia) by an experimenter blind to the condition. Three sessions of 1 Hz rTMS (600 stimuli per session) were applied at 90% of resting motor threshold [8] over left PPC every other day, using a 70 mm figure-of-eight coil and the MagStim Super Rapid stimulator (Magstim Company Ltd., Whitland, UK). A single-pulse TMS hunting procedure, using a PC-based linelength estimation task [9], was employed to functionally localize the PPC site. A nine points grid (3 3 cm) was centered over P3 and 10 stimuli were delivered at each location. The spot where TMS reversed the rightward bias in the majority of trials was found to be 1 cm anterior to P3. Clinical and behavioral evaluation was performed one week before intervention (pre 1), before rTMS on Day 1 (pre 2), after rTMS on Day 3 (post), and one week after intervention (follow-up, FU). A reduced protocol was used for pre and poststimulation evaluation on Day 2 and pre-stimulation evaluation on Day 3. It did not include line bisection and object use and the patient had to copy only two words. The patient signed a written informed consent to participate to the study, which was approved by the Local Ethical Committee. He was free from medications. Results are reported in Table 1. The rightward bisection bias was abolished after PPC stimulation as indexed by significant differences (Wilcoxon test with Bonferroni correction, P ¼ 0.05) between pre 1 and post (P ¼ 0.007), pre 2 and post (P ¼ 0.005), and pre 1 and FU (P ¼ 0.008) conditions. For handwriting, the patient received the highest performance score at baseline of Day 3 that was partly maintained at FU. On the Lickert scale, the patient did not appreciate
586 599 682 493 e (1.55) (2.01)
þ2.85 þ1.65 e 0.05 þ0.40 Pre 1 Day 1 Day 2 Day 3 FU
Results for line bisection (LB), Lickert self-evaluation scale (sign. worsening ¼ significant worsening, sign. improvement ¼ significant improvement), handwriting, use of objects (Task 1 ¼ stapler, Task 2 ¼ toothbrush, Task 3 ¼ cup of coffee, Task 4 ¼ bottle of water), and mirror dystonia (no dyst. ¼ no dystonia; max dyst. ¼ maximal dystonia). Values of left (LH) and right (RH) hemisphere resting motor threshold (RMT) are also reported. LB: mean bisection bias (mm) and relative standard deviation are reported for each experimental condition; positive values indicate rightward bisection bias and negative values leftward bisection bias. Pre ¼ pre-rTMS evaluation; Post ¼ post-rTMS evaluation; Pre 1 ¼ 1-week pre-intervention evaluation; Day 1 ¼ first day of rTMS application, Day 2 ¼ second day of application, Day 3 ¼ third day of application; FU ¼ 1-week follow-up evaluation.
RH LH
32% 32% 31% 32% 31%
Post Pre
e e 2 2 2 3 3 3 1 e 2 1 e 3 3 e e 6 7 6
2 3 e 5 3 Pre
4 5 3 7 e e e 6 7 7
Post Pre
5 5 3 8 e e e þ1 þ1 0.5
Post Pre
Signature
(1.83) (0.82)
e þ2 1 0 e
Post
Task 2 Word copy
Task 1
5 5 e 4 6
Task 3
4 5 e 3 6
Task 4
Pre
Post
(434) (376) (460) (308)
e e 514 (312) 425 (305) 615 (422)
RMT FTT (right hand RT) Mirror dystonia (0 ¼ no dyst., 5 ¼ max dyst.) Use of object (0 ¼ unable to perform, 10 ¼ normal performance) Handwriting (0 ¼ unable to perform, 10 ¼ normal performance)
Lickert scale (3 ¼ sign. worsening, þ3 ¼ sign. improvement) LB
Table 1 Clinical and behavioral evaluation and resting motor threshold.
42% 43% e 43% 43%
Letters to the Editor / Brain Stimulation 7 (2014) 909e921
913
this improvement, while reporting enhanced performance from pre 1 to pre 2, when no objective change in writing performance was observed. Regarding object use, he showed higher scores at postintervention on Tasks 1 and 2 relative to pre-treatment levels. Consistent with handwriting, mirror dystonia was scored lowest at baseline of Day 3. On the FTT, Reaction Times of the dystonic hand were (P < 0.0001) faster (Wilcoxon with Bonferroni correction) for post-stimulation of Day 3 than baseline of Day 1 conditions. Discussion Focal 1 Hz rTMS of left PPC abolished the patient’s rightward attentional bias, in line with studies in post-stroke patients [5,6]. Normalization of attentional bias was associated with improvement of dystonic symptoms, suggesting that hyper-attention toward the side of the dystonic hand contributed to the patient’s FHD. Given the tight link between PPC and PMC during intentional movement, it is likely that maladaptive plasticity, during the use of the dystonic hand, does not spare the PPC, leading to pathological increase of contralateral attention. Thus, PPC may represent a remote target site for stimulation to restore not only biased attention but also deficient premotor inhibition that has been implicated in the pathophysiology of FHD. Indeed, single-pulse TMS over PPC decreases the activity of parieto-frontal areas during modulation of visuospatial attention [9]. Lastly, the discrepancy between self-evaluation scores and handwriting performance highlights the importance of a possible dissociation between the objective reduction in FHD and subjective awareness of symptom amelioration in rTMS studies investigating patients with altered activity of premotor areas, underlying motor awareness [10]. The presence of biased spatial attention might offer a rationale for rTMS treatment over PPC in FHD. The role of attentional bias in FHD and the potential of rTMS over contralateral PPC or other interventions apt to rehabilitate attention warrant further investigation in prospective placebocontrolled trials. Competing interests: The authors report no conflicts of interest. The study was supported by a PRIN (prot. 2010ENPRYE_003) grant.
Raffaella Ricci* Department of Psychology, University of Turin, Italy Neuroscience Institute of Turin (NIT), University of Turin, Italy Adriana Salatino Department of Psychology, University of Turin, Italy Hartwig R. Siebner Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark Gaetano Mazzeo Department of Psychology, University of Turin, Italy Marcello Nobili Unit of Neurology, Koelliker Hospital, Turin, Italy * Corresponding
author. Department of Psychology, University of Turin, Via Po, 14 10123 Torino, Italy. Tel.: þ39 011 6703063. E-mail address: [email protected] Received 20 June 2014 Available online 30 August 2014
http://dx.doi.org/10.1016/j.brs.2014.07.038
914
Letters to the Editor / Brain Stimulation 7 (2014) 909e921
References [1] Siebner HR, Auer C, Conrad B. Abnormal increase in the corticomotor output to the affected hand during repetitive transcranial magnetic stimulation of the primary motor cortex in patients with writer’s cramp. Neurosci Lett 1999;262:133e6. [2] Hallett M. Neurophysiology of dystonia: the role of inhibition. Neurobiol Dis 2011;42:177e84. [3] Borich MR, Arora S, Kimberley TJ. Lasting effects of repeated rTMS application in focal hand dystonia. Restor Neurol Neurosci 2009;27:55e65. [4] Kimberley TJ, Borich MR, Arora S, et al. Multiple sessions of low-frequency repetitive transcranial magnetic stimulation in focal hand dystonia: clinical and physiological effects. Restor Neurol Neurosci 2013;31:533e42. [5] Brighina F, Bisiach E, Oliveri M, et al. 1 Hz repetitive transcranial magnetic stimulation of the unaffected hemisphere ameliorates contralesional visuospatial neglect in humans. Neurosci Lett 2003;336:131e3. [6] Salatino A, Berra E, Troni W, et al. Behavioral and neuroplastic effects of lowfrequency rTMS of the unaffected hemisphere in a chronic stroke patient: a concomitant TMS and fMRI study. Neurocase 2014 Dec;20(6):615e26. [7] Chatterjee A, Ricci R, Calhoun J. Weighing the evidence for cross over in neglect. Neuropsychologia 2000;38:1390e7. [8] Groppa S, Oliviero A, Eisen A, et al. A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2012; 123:858e82. [9] Ricci R, Salatino A, Li X, et al. Imaging the neural mechanisms of TMS neglectlike bias in healthy volunteers with the interleaved TMS/fMRI technique: preliminary evidence. Front Hum Neurosci 2012;6:326. http://dx.doi.org/10. 3389/fnhum.2012.00326. [10] Salatino A, Momo E, Nobili M, et al. Awareness of symptoms amelioration following low-frequency repetitive transcranial magnetic stimulation in a patient with Tourette syndrome and comorbid obsessive-compulsive disorder. Brain Stimul 2014;7:341e3 [Letter].
Long Term Effects of Low Frequency (10 Hz) Vagus Nerve Stimulation on EEG and Heart Rate Variability in Crohn’s Disease: A Case Report Dear Editor, We report the first clinical case of long-term low frequency vagus nerve stimulation (VNS) in a patient with Crohn’s disease (CD), a chronic inflammatory disorder characterized by relapsing and remitting periods of gastrointestinal inflammation [1]. There is no definitive cure of CD and there is a strong need for an efficient treatment inducing sustained remission. We have shown, in an experimental model of CD, that chronic low frequency VNS activates the cholinergic anti-inflammatory pathway through vagal efferents [2]. VNS is thus a therapeutic option for CD though it has only been used at high frequency in epilepsy and depression [3]. Long-term low frequency (10 Hz) VNS has never been tested in CD and its central effect remains unknown. Here, we share our first evaluation of the effect of 10 Hz VNS in CD on both brain and parasympathetic nervous system. Methods A 49 year old male adult with ileal CD since 28 years with ileocecal resection in 1986, under maintenance treatment with immunosuppressant (IMURELÒ: 200 mg/day) since 2005, was implanted with VNS in April 2012 while he was in moderate to severe flare of its CD [Crohn’s disease activity index (CDAI) of 330 (threshold ¼ 150) and ulcerated stenosis of the ileo-colonic anastomosis]. After a written informed consent, the medical team opted for a VNS protocol (http://clinical trial.gov identifier NCT01569503). Under general anesthesia, an electrode (Model 302, Cyberonics, Houston, Texas) was positioned on the left cervical VN and linked to
a stimulator (Model 102). The device was switched on at 0.5 mA the day of the surgery and increased by 0.25 mA each week until 1 mA. Stimulation parameters were: 30 s ON e 5 min OFF, 500 ms, 10 Hz. VNS was continuously performed over 12 months. EEG and electrocardiographic (ECG) recordings were performed one week before, at week 6 and months 6, 9 and 12 post VNS implantation. EEG was recorded from 96 active electrodes (Acticap, Brain products, Germany). Signals were acquired at resting state, eyes-closed, during a 20 min period and digitized at a sampling rate of 500 Hz. Data were further processed off-line using EEG Lab (sccn.ucsd.edu/eeglab) and SPM (www.fil.ion.ucl.ac.uk/spm) toolboxes. Blinks, muscular activity and VNS artifacts were removed using independent component analysis as proposed in EEG Lab. Data were re-referenced to the common average and EEG power was computed in the canonical frequency bands (delta 1e4 Hz; theta 3.5e7 Hz; alpha 7.5e13 Hz; beta 14e29 Hz; gamma 30e45 Hz) using a sliding time window of 10 s duration shifted every 5 s during the whole EEG session. For each frequency band, a Student t-test was performed to test the difference of EEG power between VNS treatment and pre-VNS period. VN activity was explored using heart rate variability (HRV) analysis from ECG recorded signal (Kubios, Finland) as we previously described [4]. A standard spectral analysis was applied on interbeat intervals using a Fast Fourier Transform. High Frequency power spectrum (HF, from 0.15 to 0.40 Hz) component was chosen to characterize parasympathetic tone fluctuations associated to VNS. Results VNS induced significant (P < 0.05) changes in resting EEG in all frequency bands with shared spatial pattern (Fig. 1). In particular, activations were observed over the mediofrontal electrodes for both low and high frequency bands with the most important activation for theta band. An additional activation was found in the occipital electrodes for the gamma band (Fig. 1A). Significant correlations (P < 0.05) were detected between EEG and HF-HRV for delta (T ¼ 3.32), theta (T ¼ 3.26), beta (T ¼ 2.75), and gamma (T ¼ 3.26) frequency bands. Interestingly, a positive correlation was observed between HF-HRV and beta-gamma bands in occipital electrodes. The highest level of significance was in the gamma band for the negative correlation between HF-HRV and EEG power on the left and right temporo-parietal electrodes (Fig. 1B). Beside these effects, the patient presented a significant clinical improvement, with a progressive decrease of the CDAI score and an endoscopic remission at month 12, associated to an increase of the parasympathetic tone as marked by the elevation of HF-HRV (Supplemental Data). Discussion To our knowledge, this is the first time that a positive effect of long-term low frequency VNS is described on EEG, HF-HRV and clinical level in a CD patient. Although we cannot completely rule out a placebo effect or even an improvement unrelated to the treatment, it is worth mentioning that the patient is still in remission after 27 months under VNS and stopping immunosuppressant at month 16. Further, we show that low frequency VNS, supposed to activate efferent fibers, also has an effect on the central nervous system as we have previously shown in rats [5]. We observed significant changes on EEG in both anterior and posterior electrodes. On anterior electrodes, the most important increase was observed in the theta band in fronto-medial electrodes. Kubota et al. [6] reported that frontal midline theta rhythm reflected high level of attentional load and was associated with an increase in both sympathetic and parasympathetic indices. Asada et al. [7] have shown that the anterior cingulate cortex (ACC) is the source of this frontal midline theta rhythm.
