The effect of sensory noise on basal ganglia
function in hypodopaminergic conditions
Filip Bergquist, MD, PhD
Dept of Neurology, Sahlgrenska University Hospital, Gothenburg Sweden
Dept of Pharmacology, University of Gothenburg, Sweden
• Exploring network activity during behaviour using
microdialysis
•
Two examples, the basal ganglia and the vestibular system
• How sensory noise may alter basal ganglia activity in
normal and dopamine depleted states
•
Sensory noise in ADHD
•
Vestibular noise in PD
Microdialysis as a tool for investigating physiological
processes in the brain of behaving animals
+ Sampling under relatively
physiological conditions, in
particular in behaving animals.
+ Multiple compounds can be
measured simultaneously
+ Local pharmacological intervention
- Poor reflexion of fast
neurotransmission
- Poor resolution in time (>5 min)
and space (>0.5x0.5 mm)
- Low throughput
Input connections
Cortex
+
+
+
+
Connections within
basal ganglia
+
Glu
Glu
Glu
Output connections
Glu
Glu
Caudate/Putamen
GABA/Enk
-
Thalamus
DA
GPe
GABA/SP/DYN
-
Glu
+
GABA
GABA
+
-
STN
-
Glu
GABA
-
-
SC
MEA
Nigral dendritic dopamine
release has a
downstream permissive
role in motor functions
Unilateral vestibular deafferentation silences the ipsilesional MVN in vivo
Why?
a) Loss of excitatory input?
b) Inbalanced commissural inhibition (Precht 1973, Ris & Godaux 1998)?
c) Combination of the two?
Eye motor
nuclei – as well as decreased sensitivity to
Increased intrinsic
excitability
inhibitory neurotransmitters (GABA, Glycin) and increased sensitivity to
Cerebellum
glutamate (NMDA, mGluR), Straka et al 2005, Darlington&Smith 2000)
(Purkinje projections)
Synaptisk reorganization – (only amphibians)
Cerebellar control
Neuromodulatory changes of synaptic inputs, e.g. via histamine
Stress-axis, cortisol
N VIII
UVD
The private synapse
The private synapse
Making Private Synapse talk
Reuptake inhibition reveals immediate GABA
imbalance following UVD
T (h)
T (h)
Flocculectomi does not alter the imbalance of
MVN GABA release after UVD
T (h)
T (h)
Commissural inhibition and the Bechterew phenomenon
After 4-5 days of compensation removing the other labyrinth leads to
UVD symptoms despite no working labyrinths. Mechanism?
Reversible ”UVD” using local anaesthesia
NNC 711
Stochastic resonance and what noise might do to the
nervous system
Stochastic resonance a.k.a.
”Noise benefit”
Increased sensory noise =>
Threshold activated systems
Improved sensory perception/detection
Appropriate levels of noise
- Can improve signal
detection
- Can improve linearity of
system response/output
- Can shift a rigid system
into a flexible one?
Collins et al 1996, Wells et al., 2005, Zeng et
al., 2000, Simonotto et al., 1999, Hidaka et al.,
2000, 2001
Improved sensorimotor integration
Mulavara et al 2011, Priplata et al 2006,
Scinariello et al 2002, Pavlik et al 1999
Improved cognition
Söderlund et al. 2007, 2010, Usher & Feingold
2000, Wilkinson et al 2005, 2008, 2010
From a peculiar class room
observation to behavioural
pharmacology and in vivo
neurochemistry, via neurocomputational modelling
Neurocomputational dopamine??
Moderate Brain Arousal-model (Sikström & Söderlund, 2007)
MBA hypotheses
Low extracellular dopamine levels produce insufficent neural noise – this
impairs signal transmission/system function.
Adding moderate noise to a low noise system will improve neural functions, if it
is not optimal to begin with.
 ”ADHD” rats respond differently to noise compared to control strains.
 ”ADHD” rats have low extracellular dopamine
 Increasing dopamine levels should shift noise-performance relation
 Decreased dopamine levels should shift noise-performance relation in
opposite direction.
Pre-pulse inhibition and acoustic noise
Pålsson et al (2010)
When dopamine reuptake is
blocked with methylphenidate
Vestibular noise effects in Parkinsonian disorders?
SVS – stochastic vestibular
stimulation
Increased mobility in patients with Parkinson’s disease or MSA
(Yamamoto et al., 2005, Pan et al., 2008)
Improved posturography in PD (Pal et al 2009)
Thresholds in higher functions – or
winner takes all
Think fast!
Choose!
- Then change
your mind!
Basal ganglia
example:
An extended filter
hypothesis
or an active selector
Stochastic vestibular stimulation
• Non invasive.
• Low amplitude (<1 mA) currents selectively activates vestibular
afferents.
• By using a noisy stimulation pattern, the vestibular system is
activated without inducing the sensation of movement (vertigo).
Cortex
Striatum
Thal
STN
Cerebellum
PPN
SNr
SVS
Possible mechanisms?
Cortex
Striatum
Thal
STN
Cerebellum
PPN
Normal
DA-denervated
Striatum
SNr
Striatum
+
+
Thal
SVS
+
–
–
SNr
Thal
++
–
SNr
↑ GLU, ↓GABA
SVS?
––
Methods
 In vivo microdialysis. Probes in SN, Stri, VM or PPN of
naïve rats and in bilat SN of 6-OHDA hemilesioned rats
 30 minutes of binaural, bipolar SVS through
subcutaneous electrodes attached over the horizontal
semicircular canals.
 Microdialysates analysed for DA and DA metabolites,
GABA, glutamate, glycine, taurine…
Frequency spectrum
4 seconds trace
Results
GABA concentrations in the
substantia nigra of unlesioned
rats increased following SVS
GABA concentrations in the
pedunculopontine nucl,
striatum and ventromedial
thalamus of unlesioned rats
Results
DA concentrations in the SN and the
striatum of unlesioned rats following
SVS
SN
SN
No significant changes
in glutamate, glycine,
glutamine taurine
Results
Bilat SN
MD probe+
Electrode
implantation
6-OHDA
lesion
Week 1
Week 2
Week 3
Week 4
Week 5
Day 1
Day 2
SVS
LDOPA
6-OHDA hemilesioned rats
- Different response in the ipsiand contralesional SN.
- L-DOPA treatment increases
nigral GABA concentrations
bilaterally.
Cortex
Striatum
Normal
Thal
Striatum
STN
Cerebellum
PPN
DA-denervated
Striatum
+
SNr
+
Thal
+
SVS
–
–
SNr
Thal
++
–
SNr
↑GABA
↑ GLU, ↓GABA
SVS
––
+L-DOPA or +SVS
+pre session SVS
Conclusions
 SVS increases GABA release in the substantia nigra.
 The increase in GABA release is DA independent.
 There is less imbalance between SN GABA release after SVS
than after LDOPA treatment.
 SVS increases rod performance as much as and more reliably
than L-DOPA, but does not alter fore paw function.
(Samoudi et al. 2011, in review)
Prospect - Clinical trial on SVS in Parkinson’s disease
Optokinetic recording of a standardized
movement (PLM)
Posturography and perturbed posturography
UPDRS symptom scoring
”L-DOPA test” (evaluation
after 12h OFF medication
and after 200 mg L-DOPA).
Double blind cross over study
of the effect of SVS in
unmedicated state and after
200 mg L-DOPA.
Acknowledgements
Supported by the Swedish Research Council, the Swedish Parkinson
Foundation, the Swedish Medical Association, Jeansons stiftelse and the
Gothenburg Medical Association