Received: 22 January 2020 

|
  Revised: 15 July 2020 
|  Accepted: 29 July 2020

DOI: 10.1111/ejn.14933

SPECIAL ISSUE ARTICLE

Feedback-dependent neuronal properties make focal dystonias so

focal

Alexey Sedov1,2   | Svetlana Usova1  | Valentin Popov1,3  | Alexey Tomskiy3  |

Hyder A. Jinnah4  | Aasef G. Shaikh5,6,7

1
Semenov Institute of Chemical Physics,
Russian Academy of Sciences, Moscow,
Abstract
Russia Focal dystonia, by definition, affects a specific body part; however, it may have a
2
Moscow Institute of Physics and widespread neural substrate. We tested this hypothesis by examining the intrinsic
Technology, Moscow Region, Russia
behaviour and the neuronal properties that are modulated by changes in the physi-
3
N. N. Burdenko National Scientific and
ological behaviour of their connections, that is feedback dependence, of the isolated
Practical Center for Neurosurgery, Moscow,
Russia pallidal neurons. During deep brain stimulation surgery in 12 patients with isolated
4
Department of Neurology, Pediatrics, and cervical dystonia (without hand involvement), we measured spontaneous as well as
Genetics, Emory University, Atlanta, GA, evoked single-unit properties in response to fist making (hand movement) or shoul-
USA
5
der shrug (neck movements). We measured the activity of isolated neurons that were
Departments of Neurology and Biomedical
Engineering, Case Western Reserve only sensitive to the neck movements, hand movement, or not responsive to hand
University, Cleveland, OH, USA or neck movements. The spontaneous firing behaviour, such as the instantaneous
6
Neurological Institute, University firing rate and its regularity, was comparable in all three types of neurons. The neck
Hospitals, Cleveland, OH, USA
7
movement-sensitive neurons had prominent bursting behaviour in comparison with
Neurology Service, Louis Stokes
Cleveland VA Medical Center, Cleveland, the hand neurons. The feedback dependence of the neck movement-sensitive neu-
OH, USA rons was also significantly impaired when compared to hand movement-sensitive
neurons. Motor-evoked change in firing rate of neck movement-sensitive neurons
Correspondence
Alexey Sedov, PhD, Laboratory of Human rapidly declined; the decay time constant was much shorter compared to hand move-
Cell Neurophysiology, Semenov Institute of ment-sensitive neurons. These results suggest that in isolated cervical dystonia, at the
Chemical Physics, 119991, Kosygina str., 4,
resolution of single neurons, the deficits are much widespread, affecting the neurons
Moscow, Russia.
Email: alexeys.sedov@gmail.com that drive the neck movement as well as the hand movements. We speculate that clin-
ically discernable dystonia occurs when additional abnormality is added to baseline
Funding information
Russian Science Foundation, Grant/Award
dysfunctional network, and one source of such abnormality may involve feedback.
Number: 18-15-00009; Russian Foundation
for Basic Research, Grant/Award Number: KEYWORDS
20-015-00438; American Academy of dystonia, globus pallidus, human brain, microelectrodes, neuronal activity
Neurology; Dystonia Medical Research
Foundation; University Hospitals, Grant/
Award Number: U54 TR001456

Abbreviations: CD, cervical dystonia; EMG, electromyography; GPe, globus pallidus externum; GPi, globus pallidus internum.

© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

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2388    
wileyonlinelibrary.com/journal/ejn Eur J Neurosci. 2021;53:2388–2397.
SEDOV et al.
1  |   IN T RO D U C T IO N
Dystonia, the third most common movement disorder, causes
a stereotyped pattern of involuntary turning or tilting of the
affected body part frequently combined with painful and
jerky or tremulous movements. Information regarding the
brain regions involved in dystonia is surprisingly limited and
often conflicting. Traditional hypotheses for the origin of
dystonia have focused on the basal ganglia (Vitek, 2002). In
contrast, contemporary theories suggested the role of an al-
tered cerebellum (Prudente, Hess, & Jinnah, 2014). Although
peripheral proprioceptors are normal in dystonia, their
modulation affects the movement characteristics (Tempel
& Perlmutter,  1990). Recent theories suggested the role of
the midbrain in the pathophysiology of dystonia (Sedov
et al., 2017). These diverse viewpoints lead to an important
suggestion that dystonia is a disorder of neural network that
is comprised of basal ganglia, cerebellum, midbrain and pe-
ripheral proprioceptors (Conte, Defazio, Hallett, Fabbrini,
& Berardelli,  2019; Cotterill, Charlesworth, Thomas,
Paulsen, & Eglen,  2016; Furuya, Uehara, Sakamoto, &
Hanakawa, 2018; Ganos et al., 2018; Georgescu et al., 2018;
Greuel et al., 2020; Hendrix & Vitek, 2012; Jinnah, Neychev,
& Hess, 2017; Jochim et al., 2018; Johnson & McIntyre, 2008;
Kohling, Koch, Hamann, & Richter,  2004; Kroneberg,
Plettig, Schneider, & Kuhn,  2018; Kuhn, Keller, Lauber,
& Taube,  2018; Legendy & Salcman,  1985; Miocinovic
et  al.,  2018; Neychev, Fan, Mitev, Hess, & Jinnah,  2008;
Neychev, Gross, Lehericy, Hess, & Jinnah,  2011; Ozturk,
Gunduz, & M, E.K., 2018; Prudente et  al.,  2014; Romeo
et  al.,  2019; Sedov, Semenova, et al., 2019; Sedov, Usova,
et al., 2019; Shakkottai et  al.,  2017; Tewari, Fremont, &
Khodakhah, 2017; Wang et al., 2018; Wilson & Hess, 2013).
In isolated cervical dystonia (CD), the abnormal neuro-
physiology that correlates with the neck movements may also
be seen in neurons responsible for the appendicular move-
ments. Behavioural, physiological and imaging literature
provided proof of this principle. Electromyography of hand
muscles in subjects with CD revealed abnormal hand muscle
activation, although the hand was not clinically involved (de
Vries et al., 2007). The fMRI activation pattern of the cere-
bral cortex during hand movements in subjects with CD, who
did not have clinical evidence for hand dystonia, was different
compared to the healthy controls (de Vries et al., 2008). The
putatively disorganized pattern of the central activation in
CD manifests in curved and irregular kinematics of clinically
non-dystonic hand; such reaching movements are even worse
when performed in an unfamiliar environment (Marinelli
et al., 2011; Nowak, Dafotakis, & Fink, 2013; Pelosin, Bove,
Marinelli, Abbruzzese, & Ghilardi, 2009).
We sought for the differences in the physiological prop-
erties of neurons correlating with the movements of dystonic
versus non-dystonic body parts at the resolution of the single
  
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   2389
units. In patients with the CD, we addressed this question
by measuring the physiology of single neurons in the vital
outflow nuclei of the basal ganglia, the globus pallidus in-
terus (GPi) and externus (GPe). A range of single-unit prop-
erties was compared. We measured the intrinsic behaviour
of the captured neurons, such as the spontaneous firing rate
and patterns. We also assessed the neuronal properties that
are driven by the feedback, that is the neuron's ability to per-
sistently maintain the change in the discharge (Myrov, Sedov,
& Belova, 2019; Sedov et al., 2017; Sedov, Semenova, et al.,
2019; Sedov, Usova, et al., 2019). We hypothesized that palli-
dal neurons responsive to clinically dystonic parts in CD, such
as the neck, will have comparable spontaneous properties as
clinically non-dystonic parts, such as the hands. The feed-
back-dependent neuronal activity, the behaviour that is mod-
ulated by the output of the motor plant, such as persistence
in firing activity, will be more affected in neck-sensitive neu-
rons compared to those sensitive to the hand movements.
2  |  M ETHODS
The institutional ethics committee at N.N. Burdenko
Neurosurgical Institute approved the study protocol. We re-
cruited 12 CD subjects who opted for deep brain stimulation
surgery of bilateral GPi due to the refractory nature of their
dystonia; 8 men (age range 32–54) and 4 women (age range
23–63) were studied. The subjects provided written consent
prior to deep brain stimulation surgery. Dystonia was pre-
sent for 2–24  years. On clinical examination, all patients
had isolated CD; there was no involvement of their hands.
Although head tremor was present in 6 patients, none had
hand tremor. The severity of dystonia was clinically deter-
mined with Toronto Western Spasmodic Torticollis Rating
Scale (TWSTRS). The score ranged between 20 and 29.
Table  1 depicts the demographics and clinical summary of
all patients that were included in this study. We excluded
those who had dystonia affecting organs other than the neck,
parkinsonism, Parkinson's disease, structural abnormalities
affecting the basal ganglia or the cerebellum, exposure to do-
pamine receptor blocking agents, active psychiatric illness,
and dementia.
Consistent with the standard of clinical care, the micro-
electrodes were advanced in the basal ganglia through the
intervening cerebral cortex, in an obliquely directed trajec-
tory, towards previously set coordinates of the pallidum.
The typical electrode track passed through the putamen, the
external pallidum, and then ending in its internal segment.
The pallidal nuclei were characterized by the electrophys-
iological signature of the constituent neurons. An increase
in the background noise and the presence of numerous cells
with high discharge rates were typical of pallidum (Vitek
et al., 1999; Vitek, Delong, Starr, Hariz, & Metman, 2011).
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2390       SEDOV et al.

T A B L E 1   The demographics and clinical summary of CD patients

Basic clinical Head Sensitive

N Gender Age Duration Diagnosis manifestation Tremor TWSTRS cells
1 m 42 3 CD Right Torticollis No 20 4
Left Laterocollis
2 f 53 6 CD Left Torticollis Jerky 23 5
3 m 44 3 CD Left Torticollis Yes 21 6
Right Laterocollis
Clonic
4 m 42 2 CD Left Torticollis Jerky 29 8
Right Laterocollis
5 m 41 2 CD Right Torticollis No 27 9
Right Laterocollis
6 f 63 6 CD Right Torticollis Yes 24 14
Left Laterocollis
7 f 40 24 CD Right Torticollis Jerky 21 3
8 m 54 5 CD Right Torticollis Jerky 24 6
9 m 42 6 CD Retrocollis No 23 11
10 f 23 6 CD Retrocollis No 25 3
11 m 32 6 CD Left Torticollis Jerky 29 3
Right Laterocollis
12 m 55 4 CD Right Laterocollis No 28 17
Right Torticollis

As the microelectrode was immersed in the brain, we found
the external segment (GPe), which is characterized by aver-
aged firing rate 53 imp/s and bursty pattern. After that, we
performed recording of background noise in the border be-
tween GPe and GPi and finally found internal segment (GPi),
which is characterized by the relatively higher firing rate (60
imp/s) and more regular pattern.
We performed analysis of perievent histograms and raster
plots of single units and electromyography (EMG) of hand
and neck muscles to identify hand and neck-sensitive neurons.
We identified three types of pallidal neurons—those with se-
lective sensitivity to neck movements, those with selective
sensitivity to hand movements, and those with no sensitivity
to hand or neck movements. For each isolated neuron, we re-
corded spontaneous single-unit activity in the absence of vol-
untary muscle activation for 30 s. Subsequently, we measured
the neuronal activity in response to voluntary movements of
the hand or neck. The neck movement was elicited by asking
patients (whose neck was secured in a stereotaxic surgical
frame) to shrug their shoulders, hence activating the trapezius
muscle. The hand movement was elicited by asking the sub-
jects to clench their fist, hence activating the finger flexors.
We simultaneously measured EMG of the rostral sub-volume
of the contralateral trapezius and hand flexor muscles using
needle electrodes. The EMG electrodes were placed after
preparing the overlying skin with alcohol. The direction of
the electrode needle was such that it remains parallel to the
muscle fibre direction. Each test was repeated for up to 10
times and then averaged in perievent histogram. The data ac-
quisition was performed with Alpha-Omega multi-channel
recording system (Alpharetta, GA, USA) during 2 simulta-
neous electrode tracks.
The single-unit activity of each neuron and EMG sig-
nals were saved on computer hard disk for offline anal-
yses. The signals were first processed with Spike 2 (CED,
Cambridge, UK) and then analysed with NeuroExplorer (Nex
Technologies, USA). EMG signals were filtered from 16 to
300 Hz with notched 50 Hz and then rectified. Bandpass filter
in the range of 100–3,000 Hz was used to prepare neurogram
that was then aligned for spike sorting. Amplitude thresh-
old (4β) was used to detect the spikes that were sorted by
means of principal component analysis (PCA) on the basis of
waveform parameters. Clustering of the spike trains was per-
formed by implementing spike density histograms (SDHs).
The analysis revealed parameters that were unique to the neu-
ronal firing pattern (Myrov et al., 2019). We used hierarchical
clustering approach using the Ward's method for merging the
branches for grouping spike trains into the patterns. We used
Jensen–Shannon divergence (JSD) as a distance metrics. The
Elbow method determined the optimal number of clusters.
Burst detection was performed with the Poisson Surprise
(PS) algorithm (Cotterill et al., 2016). The PS algorithm as-
sumes that baseline neural discharge follows a Poisson pro-
cess. The PS statistic, defined as S = −log(p) where “p” is
the probability of more or equal as “N” spikes occurring in
interval, was used to maximize the PS statistic with a surprise
SEDOV et al.
maximization algorithm (Legendy & Salcman,  1985). We
disregarded the bursts with PS lower than chosen thresh-
old. Reliably detected bursts for each isolated neuron were
then implemented to determine parameters for the burst ac-
tivity such as burst per cent (ratio of spikes in burst to the
total number of spikes) and inter-burst intervals. For burst,
pause and tonic neurons, we also analysed instantaneous fir-
ing rate, coefficient of variance of interspike interval (ISI),
and asymmetry index (median ISI/mean ISI) quantifying the
skewness of irregularity in firing discharge. For variables that
conformed to a normal distribution (Shapiro–Wilk's W test,
p > .05), we used one-way ANOVA for group comparisons.
Post hoc analysis was performed with Tukey HSD test. We
used median and quartiles for spike train statistical analysis.
Statistical analysis was performed using Matlab Statistics
toolbox (MathWorks, Natick, MA).
3  |   R E S U LTS
The overarching goal of our study was to delineate the dif-
ferences in the network physiology of the neurons that par-
ticipate in movement of dystonic organ versus the body part
that is not clinically affected by dystonia in human patients.
The specific hypothesis was that pallidal neurons respon-
sive to clinically dystonic parts in CD, such as the neck, will
have comparable spontaneous properties as clinically non-
dystonic parts, such as the hands. The feedback-dependent
neuronal activity, the behaviour that is modulated by the out-
put of the motor plant, such as persistence in firing activity,
will be more affected in neck -sensitive neurons compared
to those sensitive to the hand movements. In patients with
CD, we measured the single-unit activity of selectively neck
F I G U R E 1   Dendrogram (left panel) depicting clustering of spike train in three subtypes each with distinct neuronal firing characteristics—
such as tonic cell (top, right panel), burst neuron (middle, right panel) and pause neuron (bottom, right panel)
  
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   2391
movement-sensitive neurons and compared it with those only
responsive to hand movements, or neither sensitive to hand
or neck movements.
3.1  |  Classification and distribution of
neuronal subtypes
We analysed responses of 344 pallidal neurons (160 in GPe
and 184 in GPi) in 12 CD patients (24 hemispheres): 51 neu-
rons were responsive to neck movements, 38 were responsive
to hand movements, and 255 neither responded to neck nor to
hand movements (i.e. “non-responsive”). Further classifica-
tion of the neurons using unsupervised clustering revealed
specific characteristic that further allowed their labelling as
burst, pause and tonic neurons (Figure 1a). The pause neurons
had recurrent periods of high-frequency discharges separated
by relatively long interval of silence sometimes lasting for
up to several seconds (Figure 1b). The burst neurons had the
periods of regular burst and pause activity (Figure 1c). The
tonic neurons were classified when the cell had continuous
firing activity without intervals of silence (Figure 1d).
The survey of different types of neuronal patterns in the
globus pallidus revealed that among neck movement-sen-
sitive cells the burst units were highest in proportion (67%
in GPe; 87% in GPi) compared to tonic (9% in GPe, 6%
in GPi) and pause (24% in GPe, 7% in GPi) neurons. The
burst neurons were still more prominent among hand move-
ment-sensitive cells, but their distribution was different com-
pared to neck movement-sensitive group. Among GPe hand
movement-sensitive cells, 45% were burst neurons, 40%
were tonic cells, and 15% were pause neurons. Among GPi
hand-sensitive cells, 72% were burst cells, 17% were tonic
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2392       SEDOV et al.
cells, and 11% were pause cells. The distribution of GPi
neurons in hand movement-sensitive group was comparable
to the non-responsive neurons that were neither sensitive to
hand nor neck movement; 74% were burst, 14% were tonic,
and 12% were pause cells. GPe neurons for this group were
presented by 62% burst cells, 22% tonic cells and 16% pause
cells. Figure 2 depicts the distribution of various pallidal cell
types.
3.2  |  Intrinsic neuronal properties
In the subsequent analysis, we examined whether funda-
mental intrinsic property, the instantaneous firing rate, of
the neck movement-sensitive neurons differs compared to
those selectively responsive to hand movements. Figure 3a
provides an overview. The firing rate of neck movement-
sensitive neurons in GPi was 63 (39–79) spikes/second,
while it was 57 (43–72) spikes/second in hand movement-
sensitive cells and 62 (39–85) spikes/second in non-sensi-
tive neurons. The firing rate of neck movement-sensitive
neurons in GPe was 52 (43–71) spikes/second, while it
was 49 (41–72) spikes/second in hand movement-sensi-
tive cells and 51 (33–70) spikes/second in non-sensitive
neurons. All differences were not statistically significant
(ANOVA, p = .6).
Then, we measured differences in the firing irregularity
in neck movement sensitive versus hand movement sensitive
or non-sensitive neurons; Figure 3b provides an overview of
the firing rate coefficient of variance (CV). The CV of the
neck movement-sensitive neuron was 1.1 (1.0–1.4) in GPe
and 1.08 (1.0–1.15) in GPi, while it was 0.95 (0.7–1.3) in
F I G U R E 2   Pie chart depicting distributions of three subtypes of neuronal firing characteristics in GPe and GPi cells which were responsive to
head movements, hand movements and not responsive to head or neck
GPe and 1.1 (1.0–1.2) in GPi for hand movement sensitive
and 1.1 (0.9–1.3) in GPe and 1.0 (0.95–1.15) in GPi for
non-sensitive cells. The differences in irregularity between
movement-sensitive neurons and non-sensitive neurons were
not statistically significant (ANOVA; p = .2).
In the subsequent analysis, we asked whether the skew-
ness in the irregularity of the neuronal discharge varies ac-
cording to the neuronal subtype (neck movement sensitive,
hand movement sensitive or non-sensitive). Asymmetry
index, the ratio of the median interspike interval to mean
interspike interval, was measured for each neuron to quan-
tify the skewness of irregularity. A higher asymmetry index
suggests less skewness of irregular firing and thus more
tonic pattern. The neck movement-sensitive neurons had
significantly lower asymmetry index (0.6 (0.51–0.68)) com-
pared to both hand sensitive cells (0.7 (0.63–0.8), p = .017)
and non-responsive cells (0.65 (0.60–0.73), p  =  .03) in
GPe. At the same time, there was no significant difference
between the asymmetry index of hand movement sensitive
and non-responsive neurons (ANOVA, p  =  .09). At the
same time, there were no significant differences between
the analysed group of cells in the GPi nucleus (ANOVA,
p = .15; Figure 3c.)
Additional analysis measuring the bursting behaviour
among the neurons that are selectively responsive to neck
movements, hand movements and non-responsive focused on
burst and pause neurons. We computed burst spike per cent a
measure of a portion of total spikes that confirms the burst.
The burst spike per cent for neck movement-sensitive neurons
was 29% (23%–39%) in GPe and 24% (18%–31%) in GPi,
while it was 23% (13%–27%) in GPe and 23% (16%–32%)
in GPi for hand movement sensitive and 25% (16%–37%) in
SEDOV et al.   
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   2393

F I G U R E 3   Box plot depicting the (a) firing rate (b) coefficient of variance, (c) asymmetry index, and (d) burst spike per cent for GPe and GPi
cells. Y-axis depicts the parametric values, and each box plot depicts cell type. Horizontal line in the centre of the box plot depicts median value,
dots depict individual data values, and whiskers depict range of analysed data

GPe and 24% (17%–31%) in GPi in non-sensitive neurons
(Figure  3d). The only significant difference was found be-
tween neck and hand movement-sensitive neurons in GPe
(ANOVA; Tukey, p = .02).
In summary, in patients with isolated CD, the intrinsic
behaviour such as spontaneous firing properties of pallidal
neurons that are sensitive to neck movements (i.e. the neural
substrate that corresponds to a dystonic body part) was com-
parable to hand movement sensitive (i.e. neural substrate that
was corresponding to clinically non-dystonic body part) or
non-responsive neurons. The only exception was that neck
movement neurons had more prominent bursting behaviour
in GPe, and consistent with that fact, the measure of spike
confirming bursts and overall irregularity in the firing was
larger in these cells.
3.3  |  Feedback-dependent neuronal
properties
We subsequently analysed feedback-dependent properties
of neck movement-sensitive neurons. The persistence of
neural activity in response to the given movement is one
of the critical characteristics of the feedback integrity.
Specifically, appropriately calibrated feedback assures
persistent neural firing, while inappropriately calibrated
feedback results in the exponential decay of the neural re-
sponse. The persistence of neural firing is typically meas-
ured with the decay time constant. Figure  4a depicts an
example of hand movement-sensitive response. The dis-
charge rate of this neuron increases with fist making the ac-
tion of the hand, the response persists, and the decay time
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2394       SEDOV et al.

F I G U R E 4   Example of hand (a) and head (b) movement-sensitive neuron. Top panels depict neuronal firing raster and firing rates plotted on
y-axis and corresponding time on x-axis. The middle coloured plot and bottom line plot depict myographic activity. Myographic potential is plotted
on the y-axis while corresponding time is on the x-axis. Shaded zone is spontaneous firing, while open area is zone of evoked activity. Rightward
arrows depict start of muscle activation (fist making or shoulder shrug), while leftward arrows depict end of muscle activation (fist open or relaxing
neck). The difference in hand and head sensitive neuron is the rate at which neural firing decays, and it is much faster decay in head sensitive
neuron

summary box plots (Figure  5) depict the median time con-

stant for hand movement-sensitive neurons (2.4 s in GPe and
2.5 s in GPi) that was significantly higher (ANOVA, p = .001)
compared to neck movement-sensitive neurons (1.5 s in GPe
and 1.6  s in GPi). The results objectively confirm the per-
sistence of neural activity of hand movement-sensitive neu-
rons in response to fist making, while the decayed neural
activity of neck movement-sensitive neurons in response to
trapezius activation.

F I G U R E 5   Box plot depicting the decay time constant of head
and hand movement sensitive GPe and GPi neurons. Y-axis depicts the
parametric values, and each box plot depicts cell type. Square symbol
in the centre of the box plot depicts median value, whiskers the range
of analysed data, and the length of the box depicts interquartile interval
constant in this case is 2.2 s (the area between grey shaded
zones in Figure 4a). This phenomenon contrasts with head
movement-sensitive neuron where the activation of trape-
zius increased neural response, but the activity exponen-
tially decayed with the time constant of 0.7  s despite the
subjects are instructed to keep their shoulder shrugged (the
area between grey-shaded zone in Figure 4b).
This behaviour was consistently discovered in 51 neck
movement and 38 hand movement-sensitive neurons. The
4  |  DISCUSSION
Abnormal twisting and turning of the body part with or with-
out superimposed oscillations is a characteristic feature of
dystonia. In focal dystonia, such as CD, these features are
localized to the affected organ, that is the neck; however,
the movements of the other body parts, such as hand, is
frequently reported to be abnormal (Marinelli et  al.,  2011;
Nowak et al., 2013; Pelosin et al., 2009; Shaikh et al., 2008;
de Vries et al., 2007, 2008). Such deficits, frequently called
“pre-dystonic phase,” represent central disorganization; the
deficits are found at various levels. Peripherally, at the level
of the motor plant, the electromyography reveals abnormal
muscle activation of the non-dystonic body parts (de Vries
et al., 2007). Compared to healthy controls, the CD patients
have relatively reduced activation of bilateral parietal, left
premotor and cingulate cortex during imagined hand move-
ments. In the same patients, the activation of hand muscles,
despite the clinical absence of hand dystonia, results in im-
paired activation of ipsilateral putamen, insula, and cingulate
cortex (de Vries et al., 2008). Central disorganization results
SEDOV et al.
in abnormal kinematic properties of clinically “normal” hand
movements; deficits are present in the form of the curved and
irregular trajectory of the movements and the increased area
of movement path (Marinelli et al., 2011; Nowak et al., 2013;
Pelosin et  al.,  2009). Relatively reduced activation pattern
in response to imagined hand movements in those who do
not have hand dystonia may putatively reflect impaired cen-
tral processing of the internal representation (i.e. the inter-
nal model) of the movement to be performed. Abnormal
activation of ipsilateral putamen, insula and cingular cortex
in response to hand muscle activation further supports this
theory. Our results supported these theories at the single-unit
resolution.
In subjects with CD, without clinical evidence of hand
dystonia or hand tremor, we examined whether the physiol-
ogy of neck movement-sensitive single neurons in GPe and
GPi the outflow nuclei of the basal ganglia depict distinct
features compared to hand movement sensitive or non-re-
sponsive (to hand or neck movement) neurons. The instan-
taneous firing rate of the pallidal neurons responsive to neck
movements was not significantly different compared to those
sensitive to hand movements or non-sensitive cells. The in-
stantaneous firing rate of the neck, hand and non-sensitive
neurons was comparable to that reported in previous stud-
ies (Starr et al., 2005; Vitek, 2002; Vitek et al., 1999, 2011).
The discharge rate was lower than that reported in non-hu-
man primates (Sedov, Usova, et al., 2019; Starr et al., 2005;
Vitek et al., 2011). These results suggest that the neural firing
rate of cells that participate in the neural network that drives
clinically “non-dystonic” body parts may not be normal. This
observation is consistent with other physiological and imag-
ing evidence suggestive of the “pre-dystonic” phase that is
subclinical for the development of overt dystonia. Irregularity
of the neuronal firing pattern is another characteristic fea-
ture of dystonic neurons (Sedov, Usova, et al., 2019; Starr
et  al.,  2005; Vitek et  al.,  2011). We found irregularity and
skewness in the irregularity in the neuronal discharge pattern
in neck movement-sensitive neurons; such irregularity was
also seen in hand movement-sensitive neurons and those not
sensitive to neck or hand movements. In general scheme, we
did not find significant differences in the intrinsic neuronal
properties of the pallidal neurons that drive dystonic organ
versus that are responsive to the movements of non-dystonic
body segments. Although the trend of the distributions of the
values of asymmetry index and burst spike per cent in the
neck, hand and non-responsive neurons was comparable in
GPi and GPe, the differences among three groups reached
statistical significance only in GPe. Such differences could
be due to differences in the intrinsic membrane behaviour of
these nuclei and/or relatively limited sample size. The influ-
ence of pathological proprioception through the subthalamic
nucleus may also in part underlie such change (Jaeger & Kita,
2011; Kita & Jaeger, 2017).
  
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   2395
Persistence in neural response is thought to depend upon
fidelity of the neuronal feedback. Such feedback is critical in
motor systems where the pulse of signal responsible for the
movement is converted to the steady-state discharge repre-
senting the steady position (Sedov et al., 2017; Shaikh, Wong,
Zee, & Jinnah, 2013; Shaikh, Zee, Crawford, & Jinnah, 2016).
We had demonstrated that such feedback-dependent conver-
sion of pulse to step is impaired in subjects with dystonia;
the deficits were obvious in neck movement-sensitive neu-
rons in CD (Sedov et  al.,  2017; Sedov, Semenova, et al.,
2019; Sedov, Usova, et al., 2019; Shaikh et al., 2013). Here,
we found that the persistence in neural response measured
by decay time constant was also reduced in hand move-
ment-sensitive neurons in CD patients; however, it was still
better compared to the neck movement-sensitive neurons in
the same patient. Such differences in time constants suggest
that the feedback-dependent ability to keep persistent neural
discharge was affected in both hand and neck movement -sen-
sitive neurons, but impairment was much more severe in neck
movement-sensitive neurons.
Our results extend other physiological and imaging ev-
idence suggesting an abnormal background activity in the
pallidal single neurons responsible for driving dystonic or
non-dystonic body segments. We find comparable activity
patterns in pallidal neurons that drive dystonia and non-dys-
tonic body parts. The feedback-dependent neuronal activity
patterns are also abnormal in both cases, but the abnormality
is intensified the cells that are engaged in actively driving
clinically dystonic movements. Altogether, we speculate that
in CD there is a generalized alteration in the pallidal physi-
ology; however, the effects of such alteration are not robust
enough to account for clinical phenomenology in all body
parts. Clinically discernable dystonia occurs when the deficit
in source of the feedback is added intensifying overall net-
work dysfunction.
ACKNOWLEDGEMENTS
The study was funded by the Russian Science Foundation
(project 18-15-00009 to Sedov): MER data collection and
analysis. The study was partly supported by the Russian
Foundation for Basic Research (project 20-015-00438):
EMG analysis. This work was also supported by the
Career Development Grant from the American Academy
of Neurology (Shaikh), George C. Cotzias Memorial
Fellowship (Shaikh), Network Models in Dystonia grant
from the Dystonia Medical Research Foundation (Shaikh),
and philanthropic funds to the department of neurology at
University Hospitals (Shaikh) NIH U54 TR001456 (Jinnah).
The authors have no competing interest.
AUTHOR CONTRIBUTIONS
AS conceived the study, collected and analysed the data, and
wrote and edited the manuscript; SU, VP and AT collected
 |
2396       SEDOV et al.

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How to cite this article: Sedov A, Usova S, Popov V,
Tomskiy A, Jinnah HA, Shaikh AG. Feedback-
dependent neuronal properties make focal dystonias so
focal. Eur J Neurosci. 2021;53:2388–2397. https://doi.
org/10.1111/ejn.14933