Matt Wall, April, 2021

Neuroimaging for PsychiatristsO r …Eve r y t h i n g yo u a l ways wa nte d to k n o w a b o u t b ra i n p i c t u re s b u t we re a f ra i d to a s k

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About me

• Head of MRI applications at Invicro, London, UK• Honorary senior lecturer at Imperial College London• Honorary researcher at University College London

• Current research: Sex hormones, cannabinoids, psychedelics, methods development, reliability/reproducibility

• Likes: Big magnets, guitars, neuropsychopharmacology, Rogue One, cats.

• Dislikes: Brexit, Boris Johnson, The Rise of Skywalker, dogs.

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Neuroimaging

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Neuroimaging Technologies

• Electroencephalography (EEG)

• Computed Tomography (CT)

• Single Photon Emission Computed Tomograpy (SPECT)

• Positron Emission Tomography (PET)

• Magnetic Resonance Imaging (MRI)

• Magnetoencephalography (MEG)

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Current Neuroscience Technologies

Provide large-scale systems-level information

PET and MRI provide complementary information

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PET

• Provides precise, quantitative information about a particular compound/receptor.

• Invasive, and exposes the patient to radiation.

• Temporal and spatial resolution fairly poor.

• Sensitivity extremely high

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PET

Cyclotron Chemistry Patient Data

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PET scanners

• Thousands of detectors arranged around patient• Count many 100 millions of coincidences to determine radiotracer distribution• Scan for 60-120 minutes• Measure dynamic data

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FDG PET

• Uses [18F]Flourodeoxyglucose as a radiotracer• Routine use in oncology• Radiation accumulates in the most metabolically active tissues

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FDG PET in the brain

• Brain is very metabolically active (5% body weight, 20% oxygen consumption)

• Useful in differentiating dementia subtypes

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PET in drug development

Imaging the Drug“Biodistribution”

Imaging the Target“Occupancy”

Measures brain uptake of the radiolabelleddrug candidate

Measures the change in target availability post drug administration

Provides a measure of “free” drug concentration (VF)

Provides direct measure of target occupancy by the drug (∆VS)

Requires radiolabelling of the drug candidate with a positron emitting nucleide - often feasible

Requires a usable radioligand;more difficult than labelling a drug

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Biodistribution studies

Some species variability in CNS penetration

Rat Pig Human

Human evaluation of drug candidates:

[11C]Compound A [11C]Compound B

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Occupancy studies

Ligand Target

[11C]Carfentanil µ-Opioid

[18F]FDOPA Dopamine Synthesis

[11C]PHNO D2/D3 receptors

[11C]CIMBI-36 5HT2A receptor

[11C]UCB-J Synaptic vesicle 2 (SV2A; synaptic density)

[11C]PBR28 Translocator Protein (TSPO)

[18F]Flutemetamol ß-amyloid

[18F]T808 Tau

• Requires a suitable PET ligand (radiotracer compound):• Penetrates the BBB• Specific pharmacology• Right PK profile• Easy synthesis (ideally)

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Occupancy studies

Baseline

Plasma Conc

Occ

upan

cy

BA

RadioligandDrugTarget

BA

Post-drug

Occupancy is dose and time dependent

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MRI

• Huge, super-conducting magnet:

• 3Tesla = 30,000 Gauss (Earth magnetic field = 0.5 Gauss)

• Completely safe, if no (ferrous) metal around.

• Very flexible imaging method – multiple types of data from same patient

• Signal-to-noise-ratio (SNR) generally lower than PET

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MRI Physics

Signal (RF ‘echo’)Protons align RF pulse applied

Gradient fields

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Anatomical MRI

Provides structural information

• Many different versions available, which provide different ‘contrast’ and highlight different tissue types

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Functional MRI

• Adapts MRI to register the magnetic properties of oxygenated/deoxygenated hemoglobin, allowing imaging of real-time blood flow

• Relies on the BOLD (Blood Oxygen Level Dependent) effect

• Pros:– Can image whole brain simultaneously– Very flexible in terms of stimulus presentation– Decent spatial and temporal resolution– Can examine brain connectivity with resting-state fMRI

• Cons:– Blood flow is only an indirect correlate of brain activity– Interpretation of results can sometimes be difficult

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Bonding

Neutral

Bonding - Neutral

Task-fMRI

• Very flexible: • Audio • Video• Olfactory • Pain • Multiple response types

• Many different experimental designs possible

• Relies on ‘method of subtraction’ to isolate effects.

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Resting-state fMRI

• Brain is metabolically very active, even at rest• Spontaneous fluctuations are coherent, and

organized into spatially discrete networks:• Default-mode/task-negative• Executive/task-positive• Visual• Auditory• Language• Attention• Somatomotor

• Can be a sensitive measure of:• Development/Aging• Pathology• Acute drug effects

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Pharmacological RS-fMRI

• Effects of different types of cannabis on resting-state networks

MB Wall et al., Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity. J. Psychopharmacol. 33, 822–830 (2019).

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Drug response pathway

Tissue response

Drug in Blood

2nd MessengerResponse

Physiological/Behavioural Response

Clinical outcome

Drug in tissue

Drug at Target

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Drug response pathway

Clinical outcomeDrug in Blood

Drug in tissue

Drug at Target

2nd MessengerResponse

Tissue response

Physiological/Behavioural Response

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Drug response pathway

Clinical outcomeDrug in Blood

Drug in tissue

Drug at Target

2nd MessengerResponse

Tissue response

Physiological/Behavioural Response

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Drug response pathway

Clinical outcomeDrug in Blood

Drug in tissue

Drug at Target

2nd MessengerResponse

Tissue response

Physiological/Behavioural Response

PET (f)MRI

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What can neuroimaging do for psychiatry?

• Progress in neuroimaging has been extraordinary:

1973 2015

• Clinical treatments/outcomes in psychiatry have not progressed to the same extent

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Prof. Tom InselDirector of NiMH

(2002-2015)

“I spent 13 years at NIMH really pushing on the neuroscience and genetics of mental disorders, and when I look back on that I realize that while I think I succeeded at getting lots of really cool papers published by cool scientists at fairly large costs—I think $20 billion—I don’t think we moved the needle in reducing suicide, reducing hospitalizations, improving recovery for the tens of millions of people who have mental illness.”

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Mapping symptoms to brain featuresProblem 1: Clinical heterogeneity• Patient 1: Sleepiness/fatigue, loss of appetite, low mood, feelings of worthlessness• Patient 2: Insomnia, weight gain, anhedonia, anxiety, suicidal ideation

Same underlying dysfunction?

Problem 2: One symptom, multiple causes• Fatigue:

• Major depression• Post-viral• Stress• Endocrine problem (hypothyroidism, diabetes)• Sleep issues• Etc., etc.

Roiser, J (2015) What has neuroscience ever done for us? The Psychologist 28, 284-287. https://thepsychologist.bps.org.uk/volume-28/april-2015/what-has-neuroscience-ever-done-us

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Overlapping distributions

Hypothetical study:• Group 1: N=100 Major depression patients• Group 2: N=100 Healthy matched controls• Result: 10% less brain activity (on average) in the hippocampus of depressed subjects

Depressed ControlsPatient X

Brain imaging not useful for diagnosis.(Perhaps never will be?)

Problem is moving from statistical effects (in groups) to reliable biomarkers (in individuals)

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Schizophrenia and neuroimaging

Shepherd, et al. (2012). Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia. Neuroscience & Biobehavioral Reviews, 36(4), 1342-1356.

Giraldo-Chica, M., & Woodward, N. D. (2017). Review of thalamocortical resting-state fMRI studies in schizophrenia. Schizophrenia research, 180, 58-63.

Decreased gray matter

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Mapping prodromal psychosis

P. Fusar-Poli, P. McGuire, S. Borgwardt, Mapping prodromal psychosis: A critical review of neuroimaging studies. Eur. Psychiatry. 27, 181–191 (2012).

High riskControls

Decreased gray matterPET-fMRI integration

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PET and antipsychotics

• Patients with extrapyramidal syndromes (EPS) have higher D2 receptor occupancy (above 80%) than patients with a good clinical response but no EPS (65–80%).

Nord, M., & Farde, L. (2011). Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS neuroscience & therapeutics, 17(2), 97-103.

• Clozapine has therapeutic effects at lower levels of D2 occupancy

• Fewer EPS effects• More complex

pharmacology (higher affinity for D4R)

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Depression and neuroimaging

• Strong focus on the structure and function of the subgenual cingulate

Drevets, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 386 (1997), pp. 824–827.

FDG-PET

Greicius, et al. Resting-State Functional Connectivity in Major Depression: Abnormally Increased Contributions from Subgenual Cingulate Cortex and Thalamus. Biol. Psychiatry. 62, 429–437 (2007).

RS-fMRI

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Depression and deep brain stimulation• Electrodes implanted in the sgACC in treatment-resistant depression

Merkl et al. Antidepressant effects after short-term and chronic stimulation of the subgenual cingulate gyrus in treatment-resistant depression. Exp. Neurol. 249, 160–168 (2013).

Meta-analysis conclusion:“DBS applied to the SCC seems to be associated with relatively large response and remission rates in the short-and medium- to long-term in patients with severe TRD. ”

But:• Only open-label studies• Very high cost• Very invasive• Does not work for many patients

Berlim et al. Effectiveness and acceptability of deep brain stimulation (DBS) of the subgenual cingulate cortex for treatment-resistant depression: A systematic review and exploratory meta-analysis. J. Affect. Disord. 159, 31–38 (2014).

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Depression and psychedelics

• Recent ‘psychedelic renaissance’; research re-started after ~50 years of neglect

R. L. Carhart-Harris, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry. 3, 619–627 (2016).

RS-fMRI

R. L. Carhart-Harris, L. Roseman, M. Bolstridge, L. Demetriou, J. N. Pannekoek, M. B. Wall, et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci. Rep. 7, 13187 (2017).

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Depression and psychedelics

• First head-to-head comparison clinical trial of psilocybin vs. SSRI (escitalopram)

Carhart-Harris et al. Trial of Psilocybin versus Escitalopram for Depression. N. Engl. J. Med. (2021), doi:10.1056/NEJMoa2032994.

B

Psilo > Esc

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Wrap-up

• Neuroimaging is good basic science, but translational results have been limited

• Translation to the clinic still a topic of strong interest, and much effort

• Big role to play in novel drug development

• ‘Big data’ and machine (deep) learning hold some promise

• Other approaches (TMS, neurofeedback) may also have potential

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Question time!

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Spare/cut slides follow…

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Canonical Analysis Pipeline

Data Conversion

Slice-timeCorrection

Pre-Processing

ThresholdingVisualisation

Analysis

Motion Correction

Spatial Normalisation

Spatial Smoothing

Temporal Filtering

Modelling

Model-free analysis

Contrasts

OptionalNecessary

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Visualisation

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Task-fMRI: Kisspeptin

FSHLH

KISSPEPTIN

Testosterone/Oestrogen

Hypothalamus

Pituitary

Gonads

BBB

Kisspeptin > Placebo

A. N. Comninos, M. B. Wall, et al. Kisspeptin modulates sexual and emotional brain processing in humans. J. Clin. Invest. 127, 709–719 (2017).

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Multifactorial causation… yes… but no.

Mental IllnessGenetics

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Further resourcesHandbook of functional MRI data analysis: Poldrack, Mumford, Nichols (2011)

“What we can and cannot do with fMRI” Logothetis (2008). https://www.nature.com/articles/nature06976

”A hitchhiker’s guide to functional magnetic resonance imaging” Soares et al. (2016).https://www.frontiersin.org/articles/10.3389/fnins.2016.00515/full

Oxford neuroimaging primers: