Biology Neuroscience Article Questions Each article has its own questions. Each point corresponds to a numbered question. The numbered question is to be an

Biology Neuroscience Article Questions Each article has its own questions. Each point corresponds to a numbered question. The numbered question is to be answered. The correct answer to a numbered question will give you one point. If the answer is partially correct, partial credit will be given as a decimal value. If the answer is incorrect, no credit will be given. If the question is unanswered, no credit will be given so it is better to guess than to leave a question blank. The number of points earned will be divided by the total number of points on the exam and multiplied by 100 to get your grade. (2019) 20:20
Panther et al. BMC Neurosci
https://doi.org/10.1186/s12868-019-0503-y
RESEARCH ARTICLE
BMC Neuroscience
Open Access
Electric stimulation of the medial forebrain
bundle influences sensorimotor gaiting
in humans
Patricia Panther1,2, Maria Kuehne3, Jürgen Voges1, Sven Nullmeier4, Jörn Kaufmann3, Janet Hausmann3,
Daniel Bittner3, Imke Galazky3, Hans?Jochen Heinze3,6, Andreas Kupsch1,3,5† and Tino Zaehle3*†
Abstract
Background: Prepulse inhibition (PPI) of the acoustic startle response, a measurement of sensorimotor gaiting, is
modulated by monoaminergic, presumably dopaminergic neurotransmission. Disturbances of the dopaminergic
system can cause deficient PPI as found in neuropsychiatric diseases. A target specific influence of deep brain stimula?
tion (DBS) on PPI has been shown in animal models of neuropsychiatric disorders. In the present study, three patients
with early dementia of Alzheimer type underwent DBS of the median forebrain bundle (MFB) in a compassionate use
program to maintain cognitive abilities. This provided us the unique possibility to investigate the effects of different
stimulation conditions of DBS of the MFB on PPI in humans.
Results: Separate analysis of each patient consistently showed a frequency dependent pattern with a DBS-induced
increase of PPI at 60 Hz and unchanged PPI at 20 or 130 Hz, as compared to sham stimulation.
Conclusions: Our data demonstrate that electrical stimulation of the MFB modulates PPI in a frequency-dependent
manner. PPI measurement could serve as a potential marker for optimization of DBS settings independent of the
patient or the examiner.
Keywords: Prepulse inhibition, PPI, Medial forebrain bundle, Deep brain stimulation, DBS, Reward system,
Neuromodulation, Alzheimer’s disease
Background
Prepulse inhibition (PPI) of the acoustic startle response
(ASR) is a physiological and operational measure of the
pre-attentive filtering process known as sensorimotor gating [20]. PPI describes a reduction in the startle response amplitude, if an acoustic startling pulse
is preceded by a non-startling stimulus (prepulse) at
approximately 30 – 500 ms [12, 32]. The weak prepulse
stimulus is thought to activate a pre-attentional gating
mechanism that inhibits the startle response. Deficits in
PPI can be found in several neuropsychiatric disorders
*Correspondence: tino.zaehle@ovgu.de; tino.zaehle@med.ovgu.de
†
Andreas Kupsch and Tino Zaehle have equal contribution as senior
authors
3
Department of Neurology, University Hospital of Magdeburg, Leipziger
Str. 44, 39120 Magdeburg, Germany
Full list of author information is available at the end of the article
like schizophrenia, obsessive compulsive disorders, Huntington’s and Parkinson’s disease (PD) [4, 5, 31, 36, 44].
Also dementia of Alzheimer type (AD) is discussed to
diminish PPI [14, 27, 38]. Measurement of PPI is characterized by adequate face, predictive, and construct validity [35], but can be also modulated by attention and drugs
[9, 17]. Additionally, PPI has been shown to be directly
influenced by monoaminergic agents and is altered in
diseases associated with dopaminergic dysfunction [5,
11]. Further, baseline PPI is suggested as an important
determinant of the effect of dopamine agonists on PPI
[1]. Although it does not require learning, the expression
of PPI is regulated by higher cognitive processes [20]. A
potential link between PPI expression and cognitive performance has been suggested, such that poor PPI may
predict cognitive impairments [2]. With regard to the latter, patients with PD, which show higher levels of PPI, are
© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creat?iveco?mmons?.org/licen?ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
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and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat?iveco?mmons?.org/
publi?cdoma?in/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Panther et al. BMC Neurosci
(2019) 20:20
reported to perform better on cognitive measures, attention and processing speed than patients with lower levels
of PPI [44].
The median forebrain bundle (MFB) is a complex composition of monoaminergic fibre systems connecting
midbrain and forebrain areas (Fig. 1a, b). It is involved
in processing the dopamine dependent reward effect of
electrical self-stimulation [42]. Dopaminergic modulation has been discussed as a therapeutic option to restore
altered cortical plasticity in AD [19]. Conceivably, electrical stimulation of the MFB modulates dopaminergic
pathways and could represent a potential therapeutic
approach in AD, which we offered to three AD patients
as compassionate use.
DBS allows focal and reversible neuromodulation. Data
supports its efficacy in movement disorders, but also psychiatric diseases [15]. Finding the best stimulation setting
in patients with a DBS-System can be challenging, especially if DBS does not exert rapid therapeutic response on
the symptoms of the disease. Therefore, it is necessary
to find tools indicating a change in the cerebral network
activity which are easily and fast performed and react
quickly on changes of the programming.
Since it was shown that pharmacologic manipulations
of the dopaminergic systems alter sensorimotor gating
[5, 11, 24, 33], we investigated if PPI can be influenced
by DBS of the MFB in a stimulation frequency dependent
manner, to elucidate its potential for optimisation of DBS
setting.
Methods
Ethical standards of Human and Animal Rights were
adhered (including the Helsinki Declaration of 1975, as
revised in 2000 and 2008) and the experimental design
was approved by the local ethical committee (University
of Magdeburg, Germany; reference numbers 07/12 and
131/13). In addition, the patients gave their informed
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consent for investigations addressing the influence of
deep brain stimulation (DBS) of the MFB on PPI.
Participants
Three patients suffering from mild Alzheimer’s disease
(patient #1, female, age 79, Mini-Mental State Examination (MMSE): 27; patient #2, female, age 70, MMSE: 22;
patient #3, male, age 70, MMSE: 17; all three patients
were right handed) were offered bilateral DBS of the
MFB (Fig. 1). This treatment option is not a standard,
but a novel experimental approach in Alzheimer’s disease. Therefore DBS of the MFB was offered to these
three patients as an individual treatment as compassionate use to improve cognition in AD. The patients were
able to understand the experimental and pilot character
of the method and the risk of the medical intervention
and gave their written consent to participate in the study;
continued ability to participate in the present study has
been clinically verified by continued scientific compliance of the included patients. Furthermore, stimulation of MFB additionally offered the unique opportunity
to scientifically explore the modulation of PPI by DBS,
which was included in the written informed consent.
Patients were tested in MMST to evaluate the severity of dementia. Additionally, to exclude unsystematic
side effects during the postoperative stimulation period
of 3–6 days, we assessed an extensive cognitive testing
battery to ensure that our experimental manipulation
did not harm the patients. The cognitive tests comprising visual learning, short delayed match to sample task,
reward paradigms, Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale Cognition, geriatric
depression scale, tests for attentional performance, and
spatial memory tests, all of them did not change significantly during the short postoperative stimulation period
of 3–6 days. Finally, to exclude the possibility of a hearing
loss all patients were neurologically examined. Patients
were recruited from the Departments of Neurology and
(See figure on next page.)
Fig. 1 Schematical drawing and fiber reconstructions of the medial forebrain bundle. Schematical drawing (a) and fiber reconstruction based on
diffusion imaging of a healthy control (b) illustrating the main projections of the fasciculus telencephali (medial forebrain bundle, MFB) are shown.
Further, individual MFB reconstructions, with the corresponding electrode position for only the left side are shown for patient 1 (c sagittal-, d
axial-, e coronal sections), patient 2 (f, g, h) and patient 3 (i, j, k). The activated contact is marked in red. The MFB consists of thin, loosely arranged
ascending and descending fibers extending from septal area (SP) to the mesencephalic tegmentum. Along this route it traverses the lateral
hypothalamic area (ALH) and splits into a smaller medial and larger lateral stream at transitional zone of diencephalon and midbrain. The medial
stream (mSTR) passes through the parts of the mesencephalic and rhombencephalic tegmentum, connecting the hypothalamic centers with raphe
nuclei and medial reticular formation. On the other hand, ascending serotonergic fibers from the dorsal (DR) and medial raphe (MnR) nuclei reach
the ALH and a variety of diencephalic and telencephalic centers. The lateral stream (lSTR) connects the central nucleus of the amygdala (CeA) and
hypothalamic areas with different brain stem areas in pons and medulla oblongata. It further comprises fibers ascending from dopaminergic ventral
tegmental area (VTA) and substantia nigra pars compacta (SNc), but also fibers from noradrenergic fields like the locus coeruleus (LC) reaching
cortical and limbic regions like hippocampus (HPC), amygdala (AMY) and nucleus accumbens (NAc). MOB—main olfactory bulb, SNr—substantia
nigra pars reticulata, CN—cingulate gyrus
Panther et al. BMC Neurosci
(2019) 20:20
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Panther et al. BMC Neurosci
(2019) 20:20
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Stereotactic Neurosurgery at the University Hospital of
Magdeburg (for details cf. Table 1). Clinical diagnosis was
confirmed by D. B.
Surgery and electrical stimulation
Surgery was performed as previously described [40].
The MFB was localized using tractography and the
known anatomic relationship to the ventral tegmental
area (VTA) and subthalamic nucleus (STN) as elaborated by Coenen et al. [6]. Brain electrodes (Model 3389,
­Medtronic®, Minneapolis, MN, USA) were placed bilaterally in the superolateral branch of the MFB on both
sides under general anesthesia and connected to an
impulse generator (Activa-PC®, ­Medtronic®). Intraoperative stereotactic X-rays and postoperative CT images
documenting the electrode position were fused with
the preoperative (i.e. “planning”) MRI and tractography using Praezis-Plus® planning software (Precisis AG,
Walldorf, Germany) in order to confirm the localization of stimulation electrodes relative to the MFB (Fig. 1
and Table 2). Prior to PPI measurement the patients
were treated in 12-h intervals according to a standardized protocol: sham-stimulation followed by continuous
stimulation with 20 Hz, 60 Hz or 130 Hz in a pseudorandomized order. The pulse width was set at 90 µs and
below the occurrence of side effects (e.g. unrest, sweating, widening of the pupils, oculomotor distortion). The
stimulation voltage was increased in steps of 0.2 V every
20 min to analyse possible side effects. Depending on the
stimulation frequency, adverse effects occurred at 20 Hz
by 2.8–3.4 V, 60 Hz at 1.9–2.8 V and 130 Hz at 1.6–2.2 V.
If side effects occurred, the voltage was reduced by steps
of 0.1 V until they disappeared. An individual voltage
(see Table 2) was chosen according to appearance of
side effects. Patients showed a stable condition without
complications using a stimulation frequency at 60 Hz.
Data from the follow up will be provided in another
manuscript.
PPI data acquisition
All participants were examined in a quiet room, while
sitting in an armchair with the knees flexed, and were
asked to remain awake and relaxed. After detection
of bilateral hearing thresholds, acoustic stimuli were
binaurally presented through headphones. Each startle session comprised a modulatory prepulse stimulus
Table 1 Patient characteristics
Patient #1
Patient #2
Patient #3
Disease duration [years] 6
5
6
Medication [years]
Donepezile 10 mg [3]
Donepezile 5 mg [1]
Gingko 240 mg [0.25]
Mirtazapine 30 mg [3]
Rivastigmine 9.5 mg [2]
Citalopram 20 mg [0.75]
Rivastigmine 9.5 mg [2]
Gingko 240 mg [0.5]
Severity of dementia
Mild AD, MMSE 27
Mild AD, MMSE 22
Moderate AD, MMSE 17
Clinical course
Slowly progressive with an increase of
progression over the past year
Slowly progressive
Slowly progressive
Cognitive deficits
Encoding/consolidation memory,
spatial and temporal orientation,
executive functions
Encoding/consolidation memory,
spatial and temporal orientation,
visoconstructional skills
Encoding/consolidation memory, spatial
and temporal orientation, visocon?
structional skills, language, apraxia
MRI
Mild bilateral hippocampal atrophy
Moderate bitemporal atrophy including Global cortical atrophy
hippocampal atrophy
CSF
Amyloid beta ?
Phosphorylated tau levels ?
Amyloid beta ?
Phosphorylated tau levels ?
Amyloid beta ?
Phosphorylated tau levels ?
Table 2 Stimulation parameters
Patient #1
Right electrode
ACPC-length (mm)
24.8
Right–left (mm)
+ 6.8
Anterior–posterior (mm)
Dorsal ventral (mm)
? 3.4
? 4.7
Patient #2
Left electrode
Right electrode
? 7.7
6.9
Patient #3
Left electrode
Right electrode
? 4.6
5.8
22.4
? 3.4
? 6.5
? 1.2
? 4.9
Left electrode
27.0
±0
? 4.2
? 4.5
? 4.6
?5
? 4.5
? 5.1
Active contacts (mm)
8–, G+
1–, G+
10–, G+
1–, G+
9–, G+
0–, G+
Voltage (V)
2
2
2
1.6
1.5
2
Panther et al. BMC Neurosci
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(80 dB SPL at 1000 Hz; rise/fall time 5 ms, 30 ms duration), which preceded a startle stimulus (pulse-alone;
100 dB SPL at 1000 Hz; rise/fall time 5 ms, 30 ms burst
of pure tone) by 30, 60 or 120 ms (prepulse–pulse). The
acoustic startle session started with a 1 min acclimation
period followed by 4 initial pulse-alone trials for acclimation. These trials were not included into the analysis. Afterwards, the acquisition period was performed
with 15 pulse-alone trials and 45 prepulse–pulse trials,
presented in a pseudorandomized order. The inter-trial
intervals varied between 8 and 22 s. A 65 dB SPL broadband noise (0–44 kHz) was presented as a background
noise throughout the session that lasted approximately
20 min.
The ASR recordings were carried out at days 3–6 postsurgery, starting with the sham stimulation followed by
three separate verum stimulation conditions (20 Hz,
60 Hz, 130 Hz) at four consecutive days. PPI sessions
were performed in the morning after 12 h of continuous
stimulation at each specific stimulation frequency or no
stimulation (sham condition). The stimulation duration
of 12 h was chosen to avoid initiation effects or a possible
latency period.
Both, patients and the examiner were blinded about
the current stimulation frequency (double-blind-design).
The eye-blink component of the ASR was measured by
electromyography (EMG) recordings from pure-tin electrodes (1 cm diameter) placed below the left eye at the
inferior orbicularis oculi and at the outer canthus (lateral
orbicularis oculi muscle). EMG data were acquired continuously by using a BrainAmp amplifier system (BrainProducts, Gilching, Germany) with a sampling rate set
at 500 Hz, and signals band-limited to 250 Hz. Electrode
impedance was lower than 5 k?. Startle reflex were offline analyzed using BrainVision Analyzer 2 (BrainProducts, Gilching, Germany). The EMG raw signal was
off-line band-pass filtered between 0.5 and 20 Hz (slope
12 dB/octave) and then epoched based on the stimulus
onset with 150 ms preceding stimulus onset and 300 ms
of data poststimulus. After the segmentation the data
were baseline corrected by using a 50 ms pre-stimulus
interval. Each EMG response was visually inspected for
artefact rejection. Voluntary and spontaneous blinks
were excluded from further analysis. With a moving average of 50 ms the data were smoothed. Response peak was
defined as the point of maximal amplitude that occurred
within a window of 20–250 ms after stimulus onset. In
order to account for individual differences in startle
amplitude [24] prepulse inhibition was assessed as the
percentage of reduction of the amplitude after pulsealone trials [i.e., PPI = (PA ? PP)/PA × 100], where PA
indicates amplitude after pulse-alone trials and PP indicates the amplitude after prepulse–pulse trials.
Page 5 of 9
Data acquisition of patient scans
The scans were performed to verify the anatomical structure of MFB for stereotactic surgery individually (Fig. 1).
The MRI scans were performed on a Siemens Verio 3T
system (Siemens Medical Systems, Erlangen, Germany)
equipped with a gradient coil capable of 45 mT/m and
200 T/m/s slew rate. A standard 32-channel phased
array imaging coil was used. To increase inter-subject
reproducibility in position and minimize motion a thin
pillow was placed surrounding the sides and the back of
the head. The field of view was aligned in all cases to the
anterior commissure–posterior commissure (ac–pc) line.
Diffusion images were acquired using a twice refocused, single shot, echo planar imaging pulse sequence
using the following parameters: TE/TR = 86/10,400 ms,
matrix size = 128 × 128; 72 contiguous slices, yielding an
isotropic resolution of 2 × 2 × 2 mm3, receiver bandwidth
of 1698 Hz/pixel and an echo spacing of 0.69 ms. Diffusion weighted images were acquired along 20 non-collinear diffusion directions with b = 1000 s/mm2 and one
scan without diffusion weighting (b = 0 s/mm2) and two
averages. We allowed for parallel acquisition of independently reconstructed images using generalized auto calibrating, partially-parallel acquisitions or GRAPPA [13],
with acceleration factor of 3 and 57 reference lines. The
total acquisition time was 8 min 09 s. T1-weighted high
resolution structural MRI images were obtained using a
3D-MP RAGE sequence with the following parameters:
TE/TR = 7.21/2700 ms, TI = 1100 ms, flip angle = 7°,
receiver bandwidth = 130 Hz/pixel and a matrix size of
256 × 256 × 176, yielding to an isotropic resolution of
1 mm3. The total acquisition time was 7 min 34 s.
Data acquisition of volunteer MRI scan
MRI scans of healthy volunteers were made to demonstrate the regular anatomy and reproducibility of the
MFB (n: 11, 6?, 5?, age: 29 ± 5 years). The volunteer MRI
scan was performed on a Siemens Prisma 3T system (Siemens Medical Systems, Erlangen, Germany) equipped
with a gradient coil capable of 80 mT/m and 200 T/m/s
slew rate. A standard 64-channel phased array imaging
coil was used in receive mode.
Diffusion tensor images were acquired using a monopolar diffusion encoding, single shot, echo planar imaging pulse sequence using the following parameters: TE/
TR = 49/10,200 ms, matrix size = 138 × 138; 90 contiguous slices, yielding an isotropic resolution of
1.6 × 1.6 × 1.6 mm3, receiver bandwidth of 2012 Hz/
pixel and an echo spacing of 0.62 ms. Diffusion weighted
images were acquired along 60 non-collinear diffusion
directions with b = 1000 s/mm2 and 13 scans without
diffusion weighting (b = 0 s/mm2) equidistant distributed between the diffusion weighted scans. In order to
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correct for eddy current-induced distortions for each
gradient orientation, diffusion-weighted measurements
were acquired with both gradient polarities [3] adding up
to a total of 120 diffusion-weighted volumes. We allowed
for parallel acquisition of independently reconstructed
images using generalized auto calibrating, partially-parallel acquisitions …
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