Landau Lab

Research/Theme 03

Brain stimulation and neuromodulation

We use PET to investigate how interventions such as deep brain stimulation and vagus nerve stimulation affect brain function and molecular processes.

Deep brain · vagus nerve · electroconvulsivePETRats · minipigs · monkeys
Schematic Schematic: a train of electrical pulses reaches a site deep in the brain, and activity spreads outwards to connected regions. ELECTRICAL PULSES ELECTRODE CONNECTED REGIONS

At a glance

Main biological question
How do stimulation treatments such as deep brain stimulation, vagus nerve stimulation and electroconvulsive therapy change the brain's chemistry?
What we are investigating now
Identifying imaging measures that help explain how these treatments act, and connecting findings in animal models with clinical research.
Approaches and models
PET before and after stimulation in the same animal, which serves as its own control; tracers for noradrenaline, dopamine, serotonin, NMDA receptor channels and SV2A, with blood flow and glucose use as controls. Rats and Göttingen minipigs, using clinical devices and protocols in minipigs.
Established in published work
Acute vagus nerve stimulation in minipigs lowered [11C]yohimbine binding, consistent with noradrenaline release (Landau et al. 2015). A course of electroconvulsive stimulation raised striatal D1 binding in minipigs (Landau et al. 2018). With hippocampal DBS in minipigs, [18F]GE-179 uptake rose while blood flow did not change, which under those conditions supported activation of NMDA receptor channels (Vibholm et al. 2020). In rats, [11C]UCB-J binding was lower when injection and scanning followed ear (taVNS) stimulation; in a separate group, with [18F]FDG injected before stimulation, there was no detectable change in FDG uptake under the protocol tested (Binda et al. 2025).
Who is involved

Much of this work has been done with collaborators and former lab members. In the lab now, Joe Christensen is analysing data from the lab's deep brain stimulation study in minipigs and earlier vagus nerve stimulation (VNS) studies.

Useful collaborations
Clinical and neurosurgical groups working with stimulation treatments; device and protocol expertise; questions that need a molecular read-out of a stimulation effect. How to start a project →

01 The question

How do stimulation treatments change the brain?

Read moreShow less: How do stimulation treatments change the brain?

Electrical stimulation already treats brain disorders. Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. Deep brain stimulation (DBS) is used for movement disorders such as Parkinson's disease. Vagus nerve stimulation (VNS) is an add-on treatment for epilepsy and for treatment-resistant depression.

How these treatments act on the brain's chemistry is still not fully understood.

Our aim is to identify imaging measures that help explain how these treatments act and connect findings from animal models with clinical research.

Clinical devices and protocols, in animals we can scan.In Göttingen minipigs, the VNS device made for people can be implanted with similar stimulation settings, and courses of electroconvulsive stimulation follow the clinical protocol. Each animal is scanned before and after, and serves as its own control.

02 How we measure it

Scan, stimulate, scan again

Read moreShow less: Scan, stimulate, scan again
BASELINE PET STIMULATION PET AGAIN same animal minutes (VNS, DBS) to weeks (ECT) during, or hours to days after compare with baseline

Stimulation in our studies ranged from 30 minutes of ear stimulation to a course of 10 electroconvulsive sessions over three and a half weeks.

Which change we look for depends on the tracer. Each one asks a different question of the same brain:

[11C]yohimbineα2 adrenoceptors

Is noradrenaline being released? Binding falls when more noradrenaline competes with the tracer, a link we tested against microdialysis.

Dopamine tracersD1, D2, transporter, VMAT2

Does stimulation change dopamine signalling, at the receptors or at the nerve terminals?

[11C]MDL100,907 · [3H]DASB5-HT2A receptors · serotonin transporter

What happens to the serotonin system, measured in the living brain or in brain sections?

[18F]GE-179Open NMDA receptor channels

Are glutamate NMDA receptor channels active? The tracer binds a site inside the channel that is reached when the channel is open, so it has been proposed as a use-dependent marker. Our stimulation studies tested this with blood-flow and blocking controls (see Deep brain stimulation below).

[11C]UCB-JSV2A

Does stimulation change SV2A, a proxy for synaptic density? Theme 02 →

[18F]FDG · [15O]waterGlucose use · blood flow

Controls: did energy use or blood flow change, which could alter how much tracer reaches the tissue?

Reading a change in binding

Lower binding can mean fewer receptors, or more of the brain's own transmitter competing with the tracer. Interpreting a stimulation effect means keeping both in mind, and testing them with other measures.

03 What we found

Four ways to stimulate, and what PET showed

Read moreShow less: Four ways to stimulate, and what PET showed

Choose a stimulation method to see where it acts and what our published studies found. The tour plays on its own until you press a button.

Choose a route · four kinds of stimulationDemo playing · press to take over
DBS ELECTRODE VAGUS NERVEIN THE NECK EAR ECT ELECTRODES

Deep brain stimulation · DBS

Pulses from an electrode implanted deep in the brain

In our studies, an electrode was implanted in the hippocampus, and [18F]GE-179 PET was done with the stimulation off and on.

  1. Minipigs[18F]GE-179NMDA receptor channelsHippocampal DBS raised [18F]GE-179 uptake across the brain's grey matter by about 48% on average, while blood flow, measured with [15O]water PET, did not change, so the rise was not explained by more tracer being delivered. The authors read it as activation of NMDA receptor channels during stimulation. A blocking test with MK-801, which binds the same channel site, did not reduce uptake in the one stimulated pig tested, so blocking did not confirm channel specificity in this study.Vibholm et al., Brain Stimul 2020 · doi:10.1016/j.brs.2020.03.019
  2. Rats[18F]GE-179NMDA receptor channelsElectrical stimulation of the ventral hippocampus, strong enough to evoke epileptiform after-discharges, raised uptake at the electrode by 22% on average compared with the other side, and more than in unstimulated rats. S-ketamine, which blocks the same site in the channel, prevented the rise when given before stimulation. Under these conditions, the blocking control supports reading the rise as NMDA receptor channel activation.Vibholm et al., J Cereb Blood Flow Metab 2021 · doi:10.1177/0271678X20954928

Vagus nerve stimulation · VNS

An implanted stimulator on the vagus nerve in the neck

As in people, the stimulator was placed on the left vagus nerve. Minipigs were scanned before stimulation and again within 30 minutes of switching it on.

  1. Minipigs[11C]yohimbineα2 adrenoceptorsAcute VNS markedly reduced [11C]yohimbine binding in limbic, thalamic and cortical regions. This is consistent with noradrenaline being released and competing with the tracer, one possible explanation for the antidepressant effect of VNS.Landau et al., Brain Stimul 2015 · doi:10.1016/j.brs.2015.02.003

Transcutaneous auricular VNS · taVNS

Stimulating a branch of the vagus nerve through the ear

taVNS is a non-invasive form of vagus nerve stimulation. Healthy rats were scanned at baseline and again after 30 minutes of stimulation or sham stimulation. The two tracers were used in different rats and with different timing: [11C]UCB-J was injected and scanned straight after the stimulation, whereas [18F]FDG was injected 10 minutes before the stimulation began and imaged later, 45–75 minutes after injection. The two measurements therefore sampled different physiological windows.

  1. Rats[11C]UCB-JSV2AtaVNS lowered [11C]UCB-J binding by 36–59% in frontal cortex, striatum and midbrain, on both sides of the brain, and more than sham stimulation did.Binda et al., Psychophysiology 2025 · doi:10.1111/psyp.14709
  2. Rats[18F]FDGGlucose useNo detectable change in [18F]FDG uptake with taVNS or sham stimulation, under the protocol tested.Same study

Electroconvulsive therapy · ECT and ECS

A course of brief electrical stimulation through the scalp

In minipigs and monkeys we follow a course modelled on the clinical protocol; in rats we use electroconvulsive shocks (ECS), the animal model of ECT. The minipigs, and the monkeys in the first primate study, had no disease model.

  1. Minipigs[11C]SCH23390Dopamine D1 receptorsAfter 10 sessions over 3.5 weeks, striatal D1 binding had risen in every pig 24–48 hours later, and in most it returned towards baseline by 8–10 days. Pigs with lower binding at baseline showed larger increases.Landau et al., J Cereb Blood Flow Metab 2018 · doi:10.1177/0271678X17705260
  2. Minipigs[11C]MDL100,9075-HT2A receptorsA similar course raised binding in cortex and hippocampus 1–2 days afterwards, back towards baseline by 8–10 days, and lowered it in subcortical regions.Landau et al., J Psychopharmacol 2019 · doi:10.1177/0269881119836212
  3. MonkeysDopamine tracersTransporter · VMAT2 · D1 · D2In healthy rhesus monkeys, six ECT sessions brought early increases in striatal dopamine transporter and VMAT2 binding that returned to baseline by six weeks, and a transient rise in D1 binding; D2 binding was unaltered. In parkinsonian (MPTP-lesioned) monkeys, VMAT2 and D1 binding rose in the lesioned striatum, but dopamine transporter binding did not.Landau et al., Neuropsychopharmacology 2011 · doi · Landau et al., Neurodegener Dis 2012 · doi
  4. RatsAutoradiographyα2 adrenoceptors · serotonin transporterAfter 10 days of ECS, α2-adrenoceptor binding fell in cortical regions of Flinders Sensitive Line rats, a genetic model of depression, and of Flinders Resistant Line rats, but not Sprague–Dawley rats. Serotonin transporter binding rose after ECS in Sprague–Dawley rats only.Lillethorup et al., Eur Neuropsychopharmacol 2015 · doi · Hvilsom et al., Eur Neuropsychopharmacol 2019 · doi

Drawing: schematic, not to scale, and not any one species. Findings: the lab's published papers, as cited.

Published figure: [18F]GE-179 PET parametric images of one minipig brain in three views, baseline in the top row and during deep brain stimulation in the bottom row, on a colour scale of 0 to 7.5 millilitres per cubic centimetre. The stimulation images are much redder across the brain. Arrows mark a small increase on the implanted right side.
[18F]GE-179 PET before and during DBS. Logan parametric VT images of one minipig at baseline (DBS off, top) and during stimulation (DBS on, bottom). In this single experiment, uptake across the brain rose by 29.7%. Arrows: the small increase on the implanted right side, seen in both conditions. Colour scale 0–7.5 mL/cm³. Vibholm AK, Landau AM, Alstrup AKO, … Brooks DJ. Activation of NMDA receptor ion channels by deep brain stimulation in the pig visualised with [18F]GE-179 PET. Brain Stimul 2020;13(4):1071–1078 · Figure 4 · doi:10.1016/j.brs.2020.03.019 · CC BY-NC-ND 4.0, reproduced unmodified.
Published figure from Binda et al. 2025. Panel a: coronal rat brain slices; columns show MRI, [11C]UCB-J V_T maps at baseline, and V_T maps after taVNS, with frontal cortex, striatum and midbrain outlined; colour scale V_T 0 to 30. Panel b: time–activity curves in the left striatum over 90 minutes, baseline in black and after taVNS in red.
[11C]UCB-J PET before and after taVNS. (a) VT maps overlaid on MRI, at baseline and after 30 minutes of stimulation. (b) Radioactivity in the left striatum over 90 minutes. Binda KH, Real CC, Simonsen MT, Grove EK, Bender D, Gjedde A, Brooks DJ, Landau AM. Psychophysiology 2025;62:e14709 · Figure 3 · doi:10.1111/psyp.14709 · CC BY-NC-ND 4.0, reproduced unmodified.

04 Where next

Papers in this theme

  1. 2025
  2. 2020
    Activation of NMDA receptor ion channels by deep brain stimulation in the pig visualised with [18F]GE-179 PETPET
    Vibholm AK, Landau AM, Alstrup AKO, … Brooks DJ · Brain Stimulation
  3. 2019
  4. 2018
    Elevated dopamine D1 receptor availability in striatum of Göttingen minipigs after electroconvulsive therapyPET
    Landau AM, Alstrup AK, Audrain H, … Doudet DJ · Journal of Cerebral Blood Flow & Metabolism
  5. 2015
    Acute vagal nerve stimulation lowers α2 adrenoceptor availability: possible mechanism of therapeutic actionPET
    Landau AM, Dyve S, Jakobsen S, Alstrup AKO, Gjedde A, Doudet DJ · Brain Stimulation
  6. 2011
    Electroconvulsive therapy alters dopamine signaling in the striatum of non-human primatesPET
    Landau AM, Chakravarty MM, Clark CM, Zis AP, Doudet DJ · Neuropsychopharmacology

All brain stimulation papers →SV2A imaging (Theme 02) →

Questions for review

  1. Is "clinical devices and protocols, in animals we can scan" a fair summary of why the minipig and primate studies matter?
  2. The 2015 VNS paper is not open access. Would you send the accepted-manuscript figure file, so we could show one of its PET images here?
  3. Is the rat hippocampal stimulation study (Vibholm 2021, induced seizure activity) right under "deep brain", or would you place it separately?
  4. Should the ECT primate studies from Vancouver be featured, or kept to the publication list?

Four research themes

01Dopamine signalling and GPR6What an orphan receptor in the striatum does, and tools to image it.Visit → 02Synaptic imagingHow disease and treatments change SV2A binding, measured with UCB-J PET and autoradiography.Visit →
03Brain stimulation and neuromodulationWhat DBS, VNS and electroconvulsive stimulation change in the brain.You are here
04Neuroinflammation and glial responsesDeveloping and validating imaging tools for the brain's inflammatory and glial responses.Visit →
MethodsFrom signal to evidenceHow PET, autoradiography, tissue analyses and behaviour check one another.Read → LearnWhat can a PET scan tell us?An interactive walk-through with one tracer, [11C]UCB-J, including the taVNS study.Try the tracer studio →