this study provides class iv evidence that in patients with et treated with dbs with sid , individualized cs - ils reduces dysarthria while maintaining tremor control .
patients gave written informed consent before study participation . we hypothesized that current - shaping reduces dysarthria ( superiority : voicing and visual analog scale [ vas ] reduction ) without losing the effect on ts ( noninferiority : tremor rating scale [ trs ] and kinematic analysis of postural tremor ) .
the evidence for both research questions is classified as class iv because of the absence of a comparison group .
we screened 26 patients with et who had received a dbs system capable of ils ( activa rc / pc ; medtronic inc . ,
ten of these patients reported a deterioration of speech postoperatively and 6 ( 23% ) reported an improvement of speech ( at least 10 points on the vas ) when the dbs device was turned off and were thus included in the study ( table ; electrode localization in figure e-1 on the neurology web site at www.neurology.org ) .
patient characteristics and stimulation parameters tremor was measured using a movement analysis system ( cms 20 ; zebris medical gmbh , isny , germany ) .
the average total travel distance ( ttd ) was used for quantification of postural ( ttdpostural ) and action ( ttdaction ) tremor as described previously . in addition , patients were videotaped performing motor parts of the trs .
speech was digitally recorded in a sound - attenuated booth for the following tasks : maximum phonation time , oral diadochokinesis ( ddk ) , spontaneous speech , and a read text .
patients rated their  ability to speak  on a vas ( from 0 [ normal ] to 100 mm [ worst ] ) .
phonetic analysis was based on the ddk task as used previously , and the following parameters were measured : syllable , consonant , vowel , and closure duration ; voice - onset time ; friction and voicing during closure ; and phonation .
the electrode inducing sid ( determined by switching off the electrodes separately ) was tested on all contacts for ts from 0 to maximum 5 ma in 0.5-ma intervals . for ils ,
the most effective contact was used plus the one dorsal to it . by increasing the amplitudes in 0.5-ma intervals and using an
natick , ma ) analysis , we determined the best ts ( lowest ttdpostural ) .
the best cs - ils was determined by shifting current from the ventral to the dorsal contact in 0.5-ma steps as long as there was no recurrence of tremor ( defined as a 10% increase of the ttdpostural compared with ils ) .
stimulation was performed at frequencies of 125 hz and pulse widths of 60 s . during the ils / cs - ils condition ,
randomization was impossible because of this predefined programming algorithm . according to our hypotheses , we used 1-sided tests ( paired t test / wilcoxon signed - rank test ) for the on / off comparison . for the ils / cs - ils comparison
according to the exploratory character of this study , data were not -corrected for multiple parameters .
we hypothesized that current - shaping reduces dysarthria ( superiority : voicing and visual analog scale [ vas ] reduction ) without losing the effect on ts ( noninferiority : tremor rating scale [ trs ] and kinematic analysis of postural tremor ) .
the evidence for both research questions is classified as class iv because of the absence of a comparison group .
we screened 26 patients with et who had received a dbs system capable of ils ( activa rc / pc ; medtronic inc . ,
ten of these patients reported a deterioration of speech postoperatively and 6 ( 23% ) reported an improvement of speech ( at least 10 points on the vas ) when the dbs device was turned off and were thus included in the study ( table ; electrode localization in figure e-1 on the neurology web site at www.neurology.org ) .
tremor was measured using a movement analysis system ( cms 20 ; zebris medical gmbh , isny , germany ) .
the average total travel distance ( ttd ) was used for quantification of postural ( ttdpostural ) and action ( ttdaction ) tremor as described previously .
speech was digitally recorded in a sound - attenuated booth for the following tasks : maximum phonation time , oral diadochokinesis ( ddk ) , spontaneous speech , and a read text .
patients rated their  ability to speak  on a vas ( from 0 [ normal ] to 100 mm [ worst ] ) .
phonetic analysis was based on the ddk task as used previously , and the following parameters were measured : syllable , consonant , vowel , and closure duration ; voice - onset time ; friction and voicing during closure ; and phonation .
patients were tested with stimulation on and off . the electrode inducing sid ( determined by switching off the electrodes separately )
was tested on all contacts for ts from 0 to maximum 5 ma in 0.5-ma intervals . for ils ,
the most effective contact was used plus the one dorsal to it . by increasing the amplitudes in 0.5-ma intervals and using an
natick , ma ) analysis , we determined the best ts ( lowest ttdpostural ) .
the best cs - ils was determined by shifting current from the ventral to the dorsal contact in 0.5-ma steps as long as there was no recurrence of tremor ( defined as a 10% increase of the ttdpostural compared with ils ) .
stimulation was performed at frequencies of 125 hz and pulse widths of 60 s . during the ils / cs - ils condition ,
according to our hypotheses , we used 1-sided tests ( paired t test / wilcoxon signed - rank test ) for the on / off comparison . for the ils / cs - ils comparison , we used 1-sided tests for speech parameters and 2-sided tests for tremor parameters .
according to the exploratory character of this study , data were not -corrected for multiple parameters .
overall , patients had significantly less tremor in the on condition than in the off condition ( trs p = 0.047 , ttdpostural 
 p = 0.03 , ttdaction 
 p = 0.046 ) and a subjective deterioration of speech in stimulation on ( vas p = 0.031 ) .
in line with our previous study , the oral ddk rate also deteriorated as shown by the phonetic parameters of syllable duration ( p = 0.021 ) , vowel duration ( p = 0.026 ) , and consonant duration ( p = 0.02 ) .
logopedic evaluation showed a trend toward deterioration of speech in the ddk task during dbs on ( p = 0.063 ) . as expected ,
when comparing ils and cs - ils , patients did not show a difference in ts ( trs p = 0.50 , ttdpostural 
 p = 0.438 , ttdaction 
 p = 1.0 ) but a trend toward subjective improvement of speech during cs - ils ( 4 of 6 patients improved according to the vas , p = 0.094 ; figure 2 ) .
consistently , phonetic analysis revealed a reduction of voicing during the production of voiceless stop consonants ( p = 0.047 , figure 2 ) and also a trend toward an improvement of oral ddk rate ( syllable duration p = 0.056 , consonant duration p = 0.08 ) during cs - ils , thus reflecting reduced sid .
( a ) electrode localization and simulation of the volume of tissue activated was performed with optivise ( medtronic inc . ) for the left electrode of patient 3 during interleaving stimulation ( ils ) and current - shaping ils ( cs - ils ) conditions .
individual anatomical landmarks : the thalamus is shown in magenta , the ventral intermediate nucleus inside the thalamus in dark blue , the red nucleus in orange , the zona incerta in green , and the subthalamic nucleus in light blue .
note that with ils , the 2 pulses are not applied simultaneously to the tissue ( as implicated here ) but in a temporally alternating sequence .
( b ) in this patient , when comparing cs - ils with ils , there was an improvement of speech parameters , especially self - reported overall speech on the visual analog scale ( vas ) ( in pts [ points ] ) , with no deterioration of tremor control measured with the tremor rating scale ( trs ) and kinematic analysis of postural tremor ( ttdpostural = total travel distance of postural tremor ) .
( a ) acoustic waveform and spectrogram of one syllable /ka/ during oral diadochokinesis , showing prolonged voicing ( marked red ) during the stop consonant 's constriction phase in the stimulation on condition ( c = consonant ; v = vowel ; vot = voice onset time ) .
( b ) comparison of voicing during the production of voiceless stop consonants in interleaving stimulation ( ils ) and current - shaping ils ( cs - ils ) . voicing is reduced during cs - ils ( p = 0.047 ) , reflecting less dysarthria .
( c ) comparison of self - reported overall speech ( visual analog scale [ vas ] in points [ pts ] ) in ils and cs - ils .
there is a trend for overall speech improvement during cs - ils ( p = 0.094 ) .
this is a proof - of - principle study investigating current - shaping for reduction of sid .
this exploratory study was controlled for various aspects : first , we controlled for potential neurobiological effects of ils per se because both parameter settings were programmed in an interleaved fashion ; second , we used the same total amount of current and the same contacts in both conditions , allowing us to conclude that observed changes are solely attributable to current - shaping . furthermore , not only were tremor and speech parameters analyzed in a blinded manner , but patients were also unaware of the stimulation mode . because ils and cs - ils suppressed tremor equally well , they were indistinguishable by the patients .
furthermore , we stimulated with constant current rather than voltage - dependent in order to compensate unequal impedances of different electrode contacts .
any inferences that can be drawn from this study need to be considered in light of the small number of patients included .
however , one has to bear in mind that only 10% of patients develop sid and until now there was only a small population of patients who had been provided with an ils - capable device . in summary
, the data suggest that current - shaping , in principle , reduces side effects while maintaining the beneficial effects of dbs .
dr . barbe : study concept and design , acquisition of data , analysis and interpretation , first draft of the manuscript .
dembek : study concept and design , acquisition of data , analysis and interpretation , critical revision of the manuscript for important intellectual content .
becker : analysis and interpretation , critical revision of the manuscript for important intellectual content .
hartinger : analysis of data , critical revision of the manuscript for important intellectual content .
runge : acquisition of data , critical revision of the manuscript for important intellectual content .
timmermann : study concept and design , critical revision of the manuscript for important intellectual content , study supervision .
this investigator - initiated trial was cofinanced by an unrestricted research grant from medtronic inc . , minneapolis , mn .
this study was supported by a grant of the german research foundation ( dfg ) , clinical research group 219 ( kfo 219 ) to l.t . and g.r.f ( ti 319/2 - 1 , fi 773/8 - 1 , and schu 1439/3 - 1 ) .
m. barbe received honoraria for speaking engagements from ge medical and medtronic inc . and travel grants from medtronic inc .
j. raethjen received speaker fees from abbvie and lundbeck , and travel support from grifols .
i. meister received lecture fees from bristol - myers squibb and pfizer and royalties from thieme medical publishers .
g. fink serves as an editorial board member of cortex , neuroimage : clinical , zeitschrift fr neuropsychologie , and fortschritte der neurologie psychiatrie ; receives royalties from the publication of the book funktionelle mrt in psychiatrie und neurologie and neurologische differentialdiagnose ; received honoraria for speaking engagements from teva , glaxosmithkline , and boehringer ingelheim ; and receives research support from the bundesministerium fr bildung und forschung and the deutsche forschungsgemeinschaft .
received honoraria as a speaker on symposia sponsored by teva pharma , lundbeck pharma , bracco , gianni pr , medas pharma , ucb schwarz pharma , desitin pharma , boehringer ingelheim , glaxosmithkline , eumecom , orion pharma , medtronic , boston scientific , cephalon , abbott , ge medical , archimedes , and bayer .
personally , received funding by the german research foundation , the german ministry of education and research , manfred und ursula mller stiftung , klh stiftung , hoffnungsbaum e.v .
, nbia disorders society usa , kln fortune , medtronic , deutsche parkinson vereinigung , archimedes pharma , abbott , bayer , ucb , zur rose pharma , and teva .
 objective : to investigate in patients with essential tremor ( et ) treated with thalamic / subthalamic deep brain stimulation ( dbs ) whether stimulation - induced dysarthria ( sid ) can be diminished by individualized current - shaping with interleaving stimulation ( cs - ils ) while maintaining tremor suppression ( ts).methods : of 26 patients screened , 10 reported sid and were invited for testing . 
 ts was assessed by the tremor rating scale and kinematic analysis of postural and action tremor . 
 sid was assessed by phonetic and logopedic means . 
 additionally , patients rated their dysarthria on a visual analog scale.results:in 6 of the 10 patients with et , dbs - on ( relative to dbs - off ) led to sid while tremor was successfully reduced . 
 when comparing individualized cs - ils with a non  current - shaped interleaving stimulation ( ils ) in these patients , there was no difference in ts while 4 of the 6 patients showed subjective improvement of speech during cs - ils 
 . phonetic analysis ( ils vs cs - ils ) revealed that during cs - ils there was a reduction of voicing during the production of voiceless stop consonants and also a trend toward an improvement in oral diadochokinetic rate , reflecting less dysarthria . 
 logopedic rating showed a trend toward deterioration in the diadochokinesis task when comparing on with off but no difference between ils and cs-ils.conclusion:this is a proof - of - principle evaluation of current - shaping in patients with et treated with thalamic / subthalamic dbs and experiencing sid . 
 data suggest a benefit on sid from individual shaping of current spread while ts is preserved.classification of evidence : this study provides class iv evidence that in patients with et treated with dbs with sid , individualized cs - ils reduces dysarthria while maintaining tremor control . 
Classification of evidence:
METHODS
Standard protocol approvals, ethics, and patient consents.
Primary research questions.
Patients.
Tremor analysis.
Analysis of dysarthria.
DBS programming algorithm.
Statistics.
RESULTS
DISCUSSION
Supplementary Material
AUTHOR CONTRIBUTIONS
STUDY FUNDING
DISCLOSURE