Articles in PresS. J Neurophysiol (August 16, 2017). doi:10.1152/jn.00674.2016
1 2 3 4 5 6
Asymmetric vestibular stimulation reveals persistent disruption of motion
7
perception in unilateral vestibular lesions
8
R. Panichi1, M. Faralli, R2. Bruni1, A. Kiriakarely1, C. Occhigrossi1, A. Ferraresi1, A.M.
9
Bronstein3, V.E. Pettorossi1.
10 11 12
1Department
of Medicina Sperimentale, Sezione di Fisiologia Umana, Università di
13
Perugia, Perugia, Italy, 06129
14
2Department
15
Otorinolaringoiatria, Università di Perugia, Perugia, Italy, 06129
16
3Academic
17
Imperial College London, London, UK, W6 8RF
of Specialità Medico-Chirurgiche e Sanità Pubblica, Sezione di
Neuro-Otology, Centre for Neuroscience, Charing Cross Hospital,
18
Running title: motion perception and asymmetric vestibular stimulation
19 20 21
Corresponding author:
22
Prof. Adolfo M. Bronstein MD PhD FRCP FANA, Neuro-otology Unit, Division of
23
Brain Sciences, Imperial College London, Charing Cross Hospital.London W6 8RF,
24
[email protected]
25 26 27 28
0
Copyright © 2017 by the American Physiological Society.
29
Abstract
30
Self-motion perception was studied in patients with unilateral vestibular lesions
31
(UVL) due to acute vestibular neuritis at 1 week, 4, 8 and 12 months after the acute
32
episode. We assessed vestibularly-mediated self-motion perception by measuring
33
the error in reproducing the position of a remembered visual target at the end of 4
34
cycles of asymmetric whole-body rotation. The oscillatory stimulus consists of a
35
slow (0.09Hz) and a fast (0.38Hz) half cycle. A large error was present in UVL
36
patients when the slow half cycle was delivered towards the lesion side, but
37
minimal towards the healthy side. This asymmetry diminished over time, but it
38
remained abnormally large at 12 months. In contrast, vestibulo-ocular reflex
39
responses showed a large direction-dependent error only initially, then they
40
normalized. Normalization also occurred for conventional reflex vestibular
41
measures (caloric tests, subjective visual vertical and head shaking nystagmus) and
42
for perceptual function during symmetric rotation. Vestibular-related handicap,
43
measured with the Dizziness Handicap Inventory (DHI) at 12 months, correlated
44
with self-motion perception asymmetry but not with abnormalities in vestibulo-
45
ocular function. We conclude that 1) a persistent self-motion perceptual bias is
46
revealed by asymmetric rotation in UVLs despite vestibulo-ocular function
47
becoming symmetric over time 2) this dissociation is caused by differential
48
perceptual-reflex adaptation to high and low frequency rotations when these are
49
combined as with our asymmetric stimulus 3) the findings imply differential
50
central compensation for vestibulo-perceptual and vestibulo-ocular reflex
51
functions 4) self-motion perception disruption may mediate long-term vestibular-
52
related handicap in UVL patients.
53 54 55 56
New & Noteworthy
57
A novel vestibular stimulus, combining asymmetric slow and fast sinusoidal half
58
cycles, revealed persistent vestibulo-perceptual dysfunction in unilateral vestibular
59
lesion (UVL) patients. The compensation of motion perception after UVL was
1
60
slower than that of vestibulo ocular reflex. Perceptual but not vestibulo-ocular
61
reflex deficits correlated with dizziness-related handicap.
62 63
Keywords
64
Motion perception, asymmetric rotation, unilateral vestibular lesion, dizziness,
65
vestibular neuritis.
66
2
67
Introduction
68
Acute unilateral vestibular lesions (UVL), in man typically due to vestibular
69
neuritis, disrupt vestibular reflexes (including loss of gaze and postural stability),
70
as well as self-motion perception, represented initially by an intense rotational
71
sensation (vertigo) (Baloh 2003; Halmagy et al, 2010). After 48-72 hours symptoms
72
subside and vestibular reflexes gradually recover through a process of “central
73
vestibular compensation” which includes plastic changes in neuronal excitability,
74
up and down regulation of neurotransmitter receptors, synaptic plasticity and
75
neuronal growth (Smith and Curthoys 1989; Curthoys 2000; Dutia 2010). In
76
conjunction with the improvement of vestibular symptoms and reflexes, quality of
77
life also improves (Bergenius and Perols 1999; Kim et al, 2008; Patel et al, 2016;).
78 79
Despite these general trends, however, the degree of clinical recovery after a UVL is
80
variable and unpredictable in individual patients. This variability depends less on
81
the severity of the lesion, as measured with tests of vestibulo-ocular reflex (VOR)
82
function (degree of canal paresis (Shupak et al, 2008) or head-impulse test
83
abnormality; Palla et al, 2008, Patel et al, 2016), and more on individual differences
84
in neurological (Adamec et al, 2015), psychological (Godemann et al, 2004 ) and
85
visual psycho-physical factors (Cousins et al, 2014; 2017). However, the
86
dependence of recovery on vestibularly-mediated motion perception has been
87
neglected, despite animal physiology (Angelaki and Cullen 2008) and human
88
imaging studies (Dieterich 2007; Helmchen et al, 2009) showing significant
89
contributions by widespread cortico-subcortical structures to central vestibular
90
processing and lesion-induced neural plasticity.
91 92
Acute UVL are known to induce dissociation between vestibulo-perceptual and
93
vestibulo-ocular reflex function (Cousins et al, 2013) but, as central compensation
94
develops, these differences are reduced (Cousins et al, 2017). Recent experiments
95
however suggest that perceptual-reflex dissociations can be induced in normal
96
subjects exposed to asymmetric rotation (Panichi et al, 2011; Pettorossi et al, 2013,
97
Pettorossi and Schieppati 2015; Pettorossi et al, 2015). In the course of repetitive
3
98
asymmetric rotations, VOR responses keep or improve symmetry. Notably,
99
however, central adaptive mechanisms make self-motion perception progressively
100
more asymmetric. We postulate that activation of such central mechanisms
101
involved in asymmetric vestibular adaptation are likely to play a critical part during
102
the adaptive process of compensation after unilateral labyrinthine lesions. Thus,
103
biases in the motion perception system may persist longer than VOR biases during
104
the compensatory period and this perceptual error could be responsible for long-
105
term symptom development. This is the general hypothesis examined here.
106 107
Therefore, we investigated self-motion perception acutely and during
108
compensation after UVL by using an asymmetric rotation technique known to
109
induce a bias in central vestibular circuitry of normal subjects (Panichi et al, 2011).
110
We compared this with the responses to symmetric rotation because symmetric
111
sinusoidal rotation (perhaps due to additional motion predictive components) is
112
unlikely to reveal long-term biases in vestibular motion perception. We also
113
compared vestibulo-perceptual responses (ultimately cortically mediated) to the
114
VOR elicited with the same symmetric and asymmetric stimuli, and with
115
conventional clinical caloric, head shaking and subjective visual vertical testing.
116
Finally, to examine the hypothesis that abnormalities in vestibularly-mediated
117
motion perception may contribute to long-term dizziness, we assessed the patients’
118
subjective clinical recovery using the Dizziness Handicap Inventory (DHI; Jacobson
119
and Newman 1990; Nola et al, 2010).
4
120 121
Material and Methods
122
Participants
123
Thirty male patients aged 24-55 years (mean 42.80, SD 8.35) were enrolled in a
124
prospective study in UVL: 24 right-handed, 6 handed, 12 with vestibular deficit in
125
the left side and 18 in the right side. Thirty normal subjects (controls) were also
126
examined, age 20-55 years old, mean 39±11.3; 25 right-handed, 5 left-handed.
127
Since in our previous study on perceptual responses to asymmetric rotation in
128
normal subjects (Pettorossi et al, 2013) male participants showed less variability
129
than female, we examined only male in the present study. Patients were first seen
130
for acute dizziness between 1 January 2009 and 31 December 2013. Inclusion
131
criteria were based on signs and symptoms of vestibular neuritis described by
132
Strupp and Brandt (2009). No patient had additional auditory or CNS symptoms or
133
signs. They all received methylprednisolone for 15 days and were encouraged to
134
become progressively physically active as symptoms subsided. All patients
135
performed the standard vestibular rehabilitation program offered in our hospital.
136 137
The patients were examined four times: approximately at one week (acute phase)
138
and at 4, 8 and 12 months after the acute episode. The 30 control subjects were also
139
tested four times at the same time intervals. Subjects' consent and protocol
140
approval followed the Helsinki declaration (1964) and was approved by the ethics
141
committee of the University of Perugia. Testing was performed by a different team
142
to the one participating in data analysis, largely unaware of the research questions.
143 144
Test of self-motion perception: stimulation apparatus and recording
145
Stimulation apparatus. Subjects were seated on a rotating chair, within an
146
acoustically isolated cabin, that rotated in the horizontal plane driven by a DC
147
motor (Powertron, Contraves, Charlotte, NC, USA) servo-controlled by an angular-
148
velocity encoder (0.01.- 1 Hz, 1% accuracy). A head holder maintained the head 30°
149
down tilted to align the horizontal semicircular canals with the rotational plane of
5
150
the platform (Fig. 1). The trunk was tightly fastened to the chair. Roll and pitch
151
head displacements were prevented by a plastic collar.
152 153
The chair oscillated sinusoidally at an amplitude of 40°. The vestibular stimulus
154
used in the main experiment consisted of four cycles of asymmetric whole-body
155
oscillations in the dark with the same back and forth amplitude, but different
156
velocity (Pettorossi et al, 2013). The stimulus profile resulted from the combination
157
of two sinusoidal half-cycles of the same amplitude (40°) but different frequencies -
158
fast half cycle (Fast HC) = 0.38 Hz and slow half cycle (Slow HC) = 0.09 Hz (Fig. 1).
159
Peak acceleration during the fast half cycle was 120°/s2 with peak velocity 47°/s,
160
followed by the slow rotation in the opposite direction at a peak acceleration of
161
7°/s2, peak velocity 11°/s that returned the subject to the starting position. Both
162
peak acceleration and velocity values are above thresholds for vestibular activation
163
(Grabherr et al,2008, Seemungal et al, 2004, Valko et al, 2012). As a control
164
condition, prior to asymmetric stimulation, all subjects underwent symmetric
165
rotation (40°, 0.38 Hz and 0.09 Hz) in order to compare motion perception
166
responses to the two stimuli.
167 168
Self-motion perception recordings. We used a psychophysical tracking procedure to
169
assess self-motion perception (Siegle et al, 2009; Pettorossi et al, 2004). Before
170
starting the rotation, subjects fixated a target placed in front of them and were
171
asked to continue to imagine the same target throughout the rotation in the dark
172
with eyes closed. The target was a light spot (diameter 1 cm) projected onto the
173
wall of the dark cabin in front of the subject at 1.5 m from the eyes. The spot was
174
switched off just before rotation onset and switched back on after rotation had
175
ended. Subjects were instructed to continuously track the remembered spot in the
176
dark as if it was earth-fixed by counter-rotating the forearm partially flexed and
177
adducted to orient a hand pointer (Fig. 1) towards the remembered spot. The
178
pointer had a laser beam that was turned on at the end of rotation for measuring
179
the angular distance between the projection of the beam on the wall and the real
180
target position (final position error, FPE). All subjects reported that the procedure
6
181
felt simple and intuitive. It could be argued that the voluntary pointing task we
182
adopted may not truly reflect vestibularly-mediated self-motion perception.
183
However, similar pointing tasks using a vestibular-remembered saccade task
184
(Bloomberg et al, 1991 Nakamura and Bronstein, 1995) break down completely in
185
humans devoid of vestibular function. Indeed, the results presented here in
186
patients with unilateral vestibular lesions also indicate that the task is vestibularly
187
mediated.
188 189
During asymmetric rotation, subjects perceive the fast half cycle more vividly than
190
the slow half cycle (Pettorossi et al, 2013) and so, at the end of each session, the
191
target is erroneously represented in the direction of the slow half cycle (Fig.. 1).
192
This FPE results from the algebraic sum of single cycle errors plus additional
193
adaptation that further enhances the perception of the fast rotation and reduces
194
that of the slow rotation (Pettorossi et al, 2013). In order to assess these
195
mechanisms in UVL patients, we delivered two rounds of “four cycle asymmetric
196
stimulation” - one with the slow half cycle (Slow HC) towards the lesion side and
197
another session with the Slow HC towards the healthy side. These oppositely
198
directed asymmetrical rotations were randomly assigned in direction and
199
administered with an interval of 1 day. Since asymmetric rotation can induce long
200
lasting after-effects (Pettorossi et al, 2015; Pettorossi et al., 2013), we ascertained
201
in preliminary experiments in three UVL patients that 1day rest interval was
202
sufficient to prevent any carry over effects. The FPEs of the two “four cycle
203
rotation” were compared and the asymmetry index of the two FPEs for perceptual
204
responses was evaluated as follows: (FPE towards lesion - FPE away the lesion)
205
*100/the sum of the two FPEs.
206 207
For separately evaluating the perception to the slow and fast half cycles and
208
comparing with data from previous studies (Pettorossi et al., 2013) we recorded
209
both perceptual tracking and the VOR in 10 controls and 10 UVL patients chosen
210
for their superior tracking ability, as shown by the similarity of their tracking to the
211
shape of the stimulus, that is, without jerks and pauses. In these 10 patients and 10
7
212
control subjects, we continuously recorded on-line tracking by connecting the
213
chair-fixed pointer to a precision potentiometer (joystick, Fig. 1A), for detailed
214
analysis as in previous experiments (Pettorossi et al, 2013). Cumulative amplitude
215
of the motion perception during fast and slow half cycles were separately
216
computed by adding four half cycle responses of two rounds of “asymmetric
217
rotations”, with the Slow HC in opposite directions (i.e. towards or away from the
218
lesion). In these subjects the VOR was also recorded with bitemporal DC-EOG
219
(Pettorossi et al, 2013) in a separate session 1 day apart. Quick nystagmic
220
components were removed off-line and the cumulative amplitude of the four half
221
cycles slow phase eye movement (cumulative slow phase eye position, SPEP)
222
(Bloomberg et al, 1991; Popov et al, 1999) were computed for fast and slow
223
rotation. The asymmetry in the VOR (asymmetry index) was also evaluated after
224
two oppositely directed rounds of “4 cycle asymmetric rotations” with the formula:
225
(lesion-Slow HC cumulative SPEP - healthy-Slow HC cumulative SPEP ) *100/ the
226
sum of the two SPEPs. Signals from the pointer, EOG and chair motion were digitised
227
by a 12-bit A/D card (Labview, National Instrument, and USA) at a sampling rate of
228
500 Hz and stored for off-line analysis.
229 230
Conventional (clinical) Vestibular Tests
231
Caloric test. Irrigation was performed with the patient supine and the head raised
232
30° according to Fitzgerald-Hallpike method, with water at 44° C and subsequently
233
at 30° C for 40 seconds, five minutes apart. We measured peak slow phase eye
234
velocity 60-90 seconds after irrigation onset and applied Jongkees formula for
235
canal paresis [(right cold + right warm) – (left cold + left warm)] *100/ (right warm
236
+ left cold + left warm + right cold)] and for directional preponderance [(right warm
237
+ left cold) – (right cold + left warm) *100 /(right warm + left cold + left warm + right
238
cold)] (Jacobson et al, 1995, Jonkees et al, 1965).
239 240
Head shaking nystagmus test. With the patient seated and the head flexed 30°, the
241
head was passively rotated horizontally by +/-45° at 1 Hz for 20 seconds, followed
242
by EOG recording of any evoked nystagmus. The Head Shaking Test was considered
8
243
positive if the head shaking induced at least 2 clear post rotation nystagmic beats
244
with a peak slow phase eye velocity (SPEV) > 5 deg/s (Kamei et al, 1964).
245 246
Subjective visual vertical. We used a faintly illuminated LED bar which was placed in
247
a darkened room and set 1.50 m away, straight ahead from the seated subjects. The
248
bar (30 x 1 cm) was mounted on the wall via a central rod, around which the bar
249
could be rotated by remote control in both directions. At the upper end, there was a
250
pointer that slid with the bar on a graduated scale (Faralli et al, 2007); in which
251
0°corresponds to perfect alignment with gravity. The bar was presented tilted 45°
252
to the right or left and subjects realigned the bar to perceived verticality. Three
253
measurements per side were conducted alternating the starting position from 45°
254
right and left tilt. The mean value of the six measurements will be reported. In
255
accordance with the literature mean values of subjective visual vertical between
256
±2° were considered normal (Friedman 1970).
257 258
DHI. Clinical outcome at 12 months was assessed with the Dizziness Handicap
259
Inventory (DHI; Jacobson and Newman, 1990, Nola et al, 2010). The DHI comprises
260
25 items (questions) and three possible replies: “yes” (four points), “sometimes”
261
(two points) and “no” (zero points) designed to access a patient’s functional (nine
262
questions), emotional (nine questions) and physical (seven questions) limitations.
263
A score
1 2 3 4 5 6
Asymmetric vestibular stimulation reveals persistent disruption of motion
7
perception in unilateral vestibular lesions
8
R. Panichi1, M. Faralli, R2. Bruni1, A. Kiriakarely1, C. Occhigrossi1, A. Ferraresi1, A.M.
9
Bronstein3, V.E. Pettorossi1.
10 11 12
1Department
of Medicina Sperimentale, Sezione di Fisiologia Umana, Università di
13
Perugia, Perugia, Italy, 06129
14
2Department
15
Otorinolaringoiatria, Università di Perugia, Perugia, Italy, 06129
16
3Academic
17
Imperial College London, London, UK, W6 8RF
of Specialità Medico-Chirurgiche e Sanità Pubblica, Sezione di
Neuro-Otology, Centre for Neuroscience, Charing Cross Hospital,
18
Running title: motion perception and asymmetric vestibular stimulation
19 20 21
Corresponding author:
22
Prof. Adolfo M. Bronstein MD PhD FRCP FANA, Neuro-otology Unit, Division of
23
Brain Sciences, Imperial College London, Charing Cross Hospital.London W6 8RF,
24
[email protected]
25 26 27 28
0
Copyright © 2017 by the American Physiological Society.
29
Abstract
30
Self-motion perception was studied in patients with unilateral vestibular lesions
31
(UVL) due to acute vestibular neuritis at 1 week, 4, 8 and 12 months after the acute
32
episode. We assessed vestibularly-mediated self-motion perception by measuring
33
the error in reproducing the position of a remembered visual target at the end of 4
34
cycles of asymmetric whole-body rotation. The oscillatory stimulus consists of a
35
slow (0.09Hz) and a fast (0.38Hz) half cycle. A large error was present in UVL
36
patients when the slow half cycle was delivered towards the lesion side, but
37
minimal towards the healthy side. This asymmetry diminished over time, but it
38
remained abnormally large at 12 months. In contrast, vestibulo-ocular reflex
39
responses showed a large direction-dependent error only initially, then they
40
normalized. Normalization also occurred for conventional reflex vestibular
41
measures (caloric tests, subjective visual vertical and head shaking nystagmus) and
42
for perceptual function during symmetric rotation. Vestibular-related handicap,
43
measured with the Dizziness Handicap Inventory (DHI) at 12 months, correlated
44
with self-motion perception asymmetry but not with abnormalities in vestibulo-
45
ocular function. We conclude that 1) a persistent self-motion perceptual bias is
46
revealed by asymmetric rotation in UVLs despite vestibulo-ocular function
47
becoming symmetric over time 2) this dissociation is caused by differential
48
perceptual-reflex adaptation to high and low frequency rotations when these are
49
combined as with our asymmetric stimulus 3) the findings imply differential
50
central compensation for vestibulo-perceptual and vestibulo-ocular reflex
51
functions 4) self-motion perception disruption may mediate long-term vestibular-
52
related handicap in UVL patients.
53 54 55 56
New & Noteworthy
57
A novel vestibular stimulus, combining asymmetric slow and fast sinusoidal half
58
cycles, revealed persistent vestibulo-perceptual dysfunction in unilateral vestibular
59
lesion (UVL) patients. The compensation of motion perception after UVL was
1
60
slower than that of vestibulo ocular reflex. Perceptual but not vestibulo-ocular
61
reflex deficits correlated with dizziness-related handicap.
62 63
Keywords
64
Motion perception, asymmetric rotation, unilateral vestibular lesion, dizziness,
65
vestibular neuritis.
66
2
67
Introduction
68
Acute unilateral vestibular lesions (UVL), in man typically due to vestibular
69
neuritis, disrupt vestibular reflexes (including loss of gaze and postural stability),
70
as well as self-motion perception, represented initially by an intense rotational
71
sensation (vertigo) (Baloh 2003; Halmagy et al, 2010). After 48-72 hours symptoms
72
subside and vestibular reflexes gradually recover through a process of “central
73
vestibular compensation” which includes plastic changes in neuronal excitability,
74
up and down regulation of neurotransmitter receptors, synaptic plasticity and
75
neuronal growth (Smith and Curthoys 1989; Curthoys 2000; Dutia 2010). In
76
conjunction with the improvement of vestibular symptoms and reflexes, quality of
77
life also improves (Bergenius and Perols 1999; Kim et al, 2008; Patel et al, 2016;).
78 79
Despite these general trends, however, the degree of clinical recovery after a UVL is
80
variable and unpredictable in individual patients. This variability depends less on
81
the severity of the lesion, as measured with tests of vestibulo-ocular reflex (VOR)
82
function (degree of canal paresis (Shupak et al, 2008) or head-impulse test
83
abnormality; Palla et al, 2008, Patel et al, 2016), and more on individual differences
84
in neurological (Adamec et al, 2015), psychological (Godemann et al, 2004 ) and
85
visual psycho-physical factors (Cousins et al, 2014; 2017). However, the
86
dependence of recovery on vestibularly-mediated motion perception has been
87
neglected, despite animal physiology (Angelaki and Cullen 2008) and human
88
imaging studies (Dieterich 2007; Helmchen et al, 2009) showing significant
89
contributions by widespread cortico-subcortical structures to central vestibular
90
processing and lesion-induced neural plasticity.
91 92
Acute UVL are known to induce dissociation between vestibulo-perceptual and
93
vestibulo-ocular reflex function (Cousins et al, 2013) but, as central compensation
94
develops, these differences are reduced (Cousins et al, 2017). Recent experiments
95
however suggest that perceptual-reflex dissociations can be induced in normal
96
subjects exposed to asymmetric rotation (Panichi et al, 2011; Pettorossi et al, 2013,
97
Pettorossi and Schieppati 2015; Pettorossi et al, 2015). In the course of repetitive
3
98
asymmetric rotations, VOR responses keep or improve symmetry. Notably,
99
however, central adaptive mechanisms make self-motion perception progressively
100
more asymmetric. We postulate that activation of such central mechanisms
101
involved in asymmetric vestibular adaptation are likely to play a critical part during
102
the adaptive process of compensation after unilateral labyrinthine lesions. Thus,
103
biases in the motion perception system may persist longer than VOR biases during
104
the compensatory period and this perceptual error could be responsible for long-
105
term symptom development. This is the general hypothesis examined here.
106 107
Therefore, we investigated self-motion perception acutely and during
108
compensation after UVL by using an asymmetric rotation technique known to
109
induce a bias in central vestibular circuitry of normal subjects (Panichi et al, 2011).
110
We compared this with the responses to symmetric rotation because symmetric
111
sinusoidal rotation (perhaps due to additional motion predictive components) is
112
unlikely to reveal long-term biases in vestibular motion perception. We also
113
compared vestibulo-perceptual responses (ultimately cortically mediated) to the
114
VOR elicited with the same symmetric and asymmetric stimuli, and with
115
conventional clinical caloric, head shaking and subjective visual vertical testing.
116
Finally, to examine the hypothesis that abnormalities in vestibularly-mediated
117
motion perception may contribute to long-term dizziness, we assessed the patients’
118
subjective clinical recovery using the Dizziness Handicap Inventory (DHI; Jacobson
119
and Newman 1990; Nola et al, 2010).
4
120 121
Material and Methods
122
Participants
123
Thirty male patients aged 24-55 years (mean 42.80, SD 8.35) were enrolled in a
124
prospective study in UVL: 24 right-handed, 6 handed, 12 with vestibular deficit in
125
the left side and 18 in the right side. Thirty normal subjects (controls) were also
126
examined, age 20-55 years old, mean 39±11.3; 25 right-handed, 5 left-handed.
127
Since in our previous study on perceptual responses to asymmetric rotation in
128
normal subjects (Pettorossi et al, 2013) male participants showed less variability
129
than female, we examined only male in the present study. Patients were first seen
130
for acute dizziness between 1 January 2009 and 31 December 2013. Inclusion
131
criteria were based on signs and symptoms of vestibular neuritis described by
132
Strupp and Brandt (2009). No patient had additional auditory or CNS symptoms or
133
signs. They all received methylprednisolone for 15 days and were encouraged to
134
become progressively physically active as symptoms subsided. All patients
135
performed the standard vestibular rehabilitation program offered in our hospital.
136 137
The patients were examined four times: approximately at one week (acute phase)
138
and at 4, 8 and 12 months after the acute episode. The 30 control subjects were also
139
tested four times at the same time intervals. Subjects' consent and protocol
140
approval followed the Helsinki declaration (1964) and was approved by the ethics
141
committee of the University of Perugia. Testing was performed by a different team
142
to the one participating in data analysis, largely unaware of the research questions.
143 144
Test of self-motion perception: stimulation apparatus and recording
145
Stimulation apparatus. Subjects were seated on a rotating chair, within an
146
acoustically isolated cabin, that rotated in the horizontal plane driven by a DC
147
motor (Powertron, Contraves, Charlotte, NC, USA) servo-controlled by an angular-
148
velocity encoder (0.01.- 1 Hz, 1% accuracy). A head holder maintained the head 30°
149
down tilted to align the horizontal semicircular canals with the rotational plane of
5
150
the platform (Fig. 1). The trunk was tightly fastened to the chair. Roll and pitch
151
head displacements were prevented by a plastic collar.
152 153
The chair oscillated sinusoidally at an amplitude of 40°. The vestibular stimulus
154
used in the main experiment consisted of four cycles of asymmetric whole-body
155
oscillations in the dark with the same back and forth amplitude, but different
156
velocity (Pettorossi et al, 2013). The stimulus profile resulted from the combination
157
of two sinusoidal half-cycles of the same amplitude (40°) but different frequencies -
158
fast half cycle (Fast HC) = 0.38 Hz and slow half cycle (Slow HC) = 0.09 Hz (Fig. 1).
159
Peak acceleration during the fast half cycle was 120°/s2 with peak velocity 47°/s,
160
followed by the slow rotation in the opposite direction at a peak acceleration of
161
7°/s2, peak velocity 11°/s that returned the subject to the starting position. Both
162
peak acceleration and velocity values are above thresholds for vestibular activation
163
(Grabherr et al,2008, Seemungal et al, 2004, Valko et al, 2012). As a control
164
condition, prior to asymmetric stimulation, all subjects underwent symmetric
165
rotation (40°, 0.38 Hz and 0.09 Hz) in order to compare motion perception
166
responses to the two stimuli.
167 168
Self-motion perception recordings. We used a psychophysical tracking procedure to
169
assess self-motion perception (Siegle et al, 2009; Pettorossi et al, 2004). Before
170
starting the rotation, subjects fixated a target placed in front of them and were
171
asked to continue to imagine the same target throughout the rotation in the dark
172
with eyes closed. The target was a light spot (diameter 1 cm) projected onto the
173
wall of the dark cabin in front of the subject at 1.5 m from the eyes. The spot was
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switched off just before rotation onset and switched back on after rotation had
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ended. Subjects were instructed to continuously track the remembered spot in the
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dark as if it was earth-fixed by counter-rotating the forearm partially flexed and
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adducted to orient a hand pointer (Fig. 1) towards the remembered spot. The
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pointer had a laser beam that was turned on at the end of rotation for measuring
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the angular distance between the projection of the beam on the wall and the real
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target position (final position error, FPE). All subjects reported that the procedure
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felt simple and intuitive. It could be argued that the voluntary pointing task we
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adopted may not truly reflect vestibularly-mediated self-motion perception.
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However, similar pointing tasks using a vestibular-remembered saccade task
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(Bloomberg et al, 1991 Nakamura and Bronstein, 1995) break down completely in
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humans devoid of vestibular function. Indeed, the results presented here in
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patients with unilateral vestibular lesions also indicate that the task is vestibularly
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mediated.
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During asymmetric rotation, subjects perceive the fast half cycle more vividly than
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the slow half cycle (Pettorossi et al, 2013) and so, at the end of each session, the
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target is erroneously represented in the direction of the slow half cycle (Fig.. 1).
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This FPE results from the algebraic sum of single cycle errors plus additional
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adaptation that further enhances the perception of the fast rotation and reduces
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that of the slow rotation (Pettorossi et al, 2013). In order to assess these
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mechanisms in UVL patients, we delivered two rounds of “four cycle asymmetric
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stimulation” - one with the slow half cycle (Slow HC) towards the lesion side and
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another session with the Slow HC towards the healthy side. These oppositely
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directed asymmetrical rotations were randomly assigned in direction and
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administered with an interval of 1 day. Since asymmetric rotation can induce long
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lasting after-effects (Pettorossi et al, 2015; Pettorossi et al., 2013), we ascertained
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in preliminary experiments in three UVL patients that 1day rest interval was
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sufficient to prevent any carry over effects. The FPEs of the two “four cycle
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rotation” were compared and the asymmetry index of the two FPEs for perceptual
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responses was evaluated as follows: (FPE towards lesion - FPE away the lesion)
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*100/the sum of the two FPEs.
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For separately evaluating the perception to the slow and fast half cycles and
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comparing with data from previous studies (Pettorossi et al., 2013) we recorded
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both perceptual tracking and the VOR in 10 controls and 10 UVL patients chosen
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for their superior tracking ability, as shown by the similarity of their tracking to the
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shape of the stimulus, that is, without jerks and pauses. In these 10 patients and 10
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control subjects, we continuously recorded on-line tracking by connecting the
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chair-fixed pointer to a precision potentiometer (joystick, Fig. 1A), for detailed
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analysis as in previous experiments (Pettorossi et al, 2013). Cumulative amplitude
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of the motion perception during fast and slow half cycles were separately
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computed by adding four half cycle responses of two rounds of “asymmetric
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rotations”, with the Slow HC in opposite directions (i.e. towards or away from the
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lesion). In these subjects the VOR was also recorded with bitemporal DC-EOG
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(Pettorossi et al, 2013) in a separate session 1 day apart. Quick nystagmic
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components were removed off-line and the cumulative amplitude of the four half
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cycles slow phase eye movement (cumulative slow phase eye position, SPEP)
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(Bloomberg et al, 1991; Popov et al, 1999) were computed for fast and slow
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rotation. The asymmetry in the VOR (asymmetry index) was also evaluated after
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two oppositely directed rounds of “4 cycle asymmetric rotations” with the formula:
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(lesion-Slow HC cumulative SPEP - healthy-Slow HC cumulative SPEP ) *100/ the
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sum of the two SPEPs. Signals from the pointer, EOG and chair motion were digitised
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by a 12-bit A/D card (Labview, National Instrument, and USA) at a sampling rate of
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500 Hz and stored for off-line analysis.
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Conventional (clinical) Vestibular Tests
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Caloric test. Irrigation was performed with the patient supine and the head raised
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30° according to Fitzgerald-Hallpike method, with water at 44° C and subsequently
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at 30° C for 40 seconds, five minutes apart. We measured peak slow phase eye
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velocity 60-90 seconds after irrigation onset and applied Jongkees formula for
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canal paresis [(right cold + right warm) – (left cold + left warm)] *100/ (right warm
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+ left cold + left warm + right cold)] and for directional preponderance [(right warm
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+ left cold) – (right cold + left warm) *100 /(right warm + left cold + left warm + right
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cold)] (Jacobson et al, 1995, Jonkees et al, 1965).
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Head shaking nystagmus test. With the patient seated and the head flexed 30°, the
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head was passively rotated horizontally by +/-45° at 1 Hz for 20 seconds, followed
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by EOG recording of any evoked nystagmus. The Head Shaking Test was considered
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positive if the head shaking induced at least 2 clear post rotation nystagmic beats
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with a peak slow phase eye velocity (SPEV) > 5 deg/s (Kamei et al, 1964).
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Subjective visual vertical. We used a faintly illuminated LED bar which was placed in
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a darkened room and set 1.50 m away, straight ahead from the seated subjects. The
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bar (30 x 1 cm) was mounted on the wall via a central rod, around which the bar
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could be rotated by remote control in both directions. At the upper end, there was a
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pointer that slid with the bar on a graduated scale (Faralli et al, 2007); in which
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0°corresponds to perfect alignment with gravity. The bar was presented tilted 45°
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to the right or left and subjects realigned the bar to perceived verticality. Three
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measurements per side were conducted alternating the starting position from 45°
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right and left tilt. The mean value of the six measurements will be reported. In
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accordance with the literature mean values of subjective visual vertical between
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±2° were considered normal (Friedman 1970).
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DHI. Clinical outcome at 12 months was assessed with the Dizziness Handicap
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Inventory (DHI; Jacobson and Newman, 1990, Nola et al, 2010). The DHI comprises
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25 items (questions) and three possible replies: “yes” (four points), “sometimes”
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(two points) and “no” (zero points) designed to access a patient’s functional (nine
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questions), emotional (nine questions) and physical (seven questions) limitations.
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A score
