Core Readings W1 — The search for imaging biomarkers in psychiatric disorders

What is the goal of medicine and how does it relate to psychiatry?

Medicine is moving toward the use of biomarkers for individualized care optimization. This poses a particular challenge for psychiatry where diagnosis relies on descriptive behaviors without objective tests for patient stratification.

How can neuroimaging techniques contribute to psychiatry?

By offering an opportunity to shift psychiatry from subjective classification to objective brain-based measures.

Why is the development of robust biomarkers crucial for psychiatry?

The success of biomarker development is crucial because it will enable psychiatry to advance into the era of modern medicine.

What is the precision-medicine initiative and how does it relate to biomarkers?

Supported by the White House in January 2015, it aims for treatment and prevention tailored to individuals' genes environment and lifestyle heavily relying on genetic or other biomarkers.

How is the personalized stratification approach revolutionizing cancer treatment?

Revolutionizing cancer treatment through novel drugs targeting specific molecular-signaling pathways related to genetic mutations allowing treatments to be tailored to a patient's genomic profile.

Why is precision medicine more challenging in psychiatry compared to neurology?

Because the path from genes to behaviours involves complex interactive links that are not yet fully understood.

What is the impact of psychiatric disorders on personal social and financial burdens?

In the USA. medical costs were estimated at $57 billion in 2006 with indirect costs from lost earnings reaching $193 billion annually.

How can biomarkers help reduce the costs associated with psychiatric disorders?

By helping reduce the staggering costs associated with psychiatric disorders by enabling better and earlier detection and improved treatment.

What are the two types of biomarkers mentioned and how do they relate to neuroimaging?

Diagnostic biomarkers, which index biological processes associated with health or disease & predictive, which reflect therapeutic response. Neuroimaging with PET or MRI can measure phenotypic variations in molecular and cellular targets or specific brain circuits satisfying both goals.

What is the basis of psychiatric disorders according to standard nosology?

Combinations of symptoms alone.

What is the hope regarding neuroimaging in the context of psychiatric diagnoses?

It could provide biomarkers that would ultimately support any nosological diagnostic classification on the basis of objective tests as in other areas of medicine. These might be part of a panel of tests that include nonimaging modalities for example genetic peripheral blood-based or cognitive tests.

What is the Research Domain Criteria (RDoC) approach?

A new way of classifying mental disorders based on dimensions of observable behaviour and neurobiological measures. It aims to identify valid elements such as genes molecules, cells circuits, physiological measures or behaviour that are associated with specific cognitive constructs across different systems.

How does neuroimaging fit within the RDoC approach?

Neuroimaging such as PET and single photon emission computed tomography (SPECT) radiotracer studies and magnetic resonance spectroscopy (MRS) fits well within this approach because it can identify biomarkers related to the cells and circuits although the results of these studies are not always direct or easily interpretable from a biological perspective.

What can Diffusion tensor imaging (DTI) techniques produce?

Images of anatomical pathways and circuits.

How can the Research Domain Criteria (RDoC) approach aid in the search for biomarkers?

By identifying neuroimaging markers of cognitive functions that may be impaired across psychiatric conditions.

What is a major challenge for the identification of imaging biomarkers for psychiatric disease?

Many of the pathological features of psychiatric disease may be subtle and elusive to neuroimaging. Task-based assessment or other challenge paradigms are essential for revealing characteristic patterns that could lead to the development of biomarkers. The discovery of biomarkers is also limited by the availability of imaging tools including the development of novel tracers for uncharted molecular targets such as tracers for neuroinflammation.

What is one explanation for the paucity of replicated imaging findings?

Attempts at replication are seldom the focus of imaging studies as the field rewards novelty over replication. Additionally the neuroimaging field remains in the mechanistic discovery phase wherein more effort is focused on uncovering alterations in imaging measures than on pursuing promising biomarkers.

What are some challenges in developing imaging biomarkers for psychiatric disease?

Inherent heterogeneity of psychiatric illnesses, a lack of objective validation measures and a need for longitudinal follow-up to establish a definitive diagnosis or clinical outcome.

What is needed to generate a larger pool of potential biomarkers?

Replication using identical paradigms in well-powered studies be accepted as the norm + systematic search to uncover additional candidates potentially through initiatives like precision-medicine studies or systematic imaging of patients with specific DSM diagnoses across multiple sites and imaging modalities.

How can imaging biomarkers be validated?

Through comparison of a prediction with an actual outcome (diagnostic histologic or therapeutic). It requires correlative analyses of in vivo imaging measures against in vitro measures. Longitudinal follow-up may be needed to establish a final diagnosis.

What characteristics are important for a biomarker to be useful in clinical practice?

Acceptable level of sensitivity specificity and predictive value be easily accessible and practically feasible easily quantifiable and cost effective.

How can the field advance the discovery and validation of imaging biomarkers?

By adopting methods that are simple reliable and easy to implement. A database of healthy individuals should be collected from each scanner to provide normative values and derive thresholds that separate health from illness.

What are imaging phantoms used for in multisite imaging studies?

Imaging phantoms which are models of brain anatomy or chemical composition are used to optimize signal-to-noise ratios on each scanner and test reproducibility across sites.

What are some requirements for standardized procedures in multisite imaging studies?

Inclusion of quality-assurance tests before data acquisition, specific analysis software for data processing and specific protocols for subject preparation (e.g. fasting).

What is the purpose of de-identifying and sharing data sets across sites?

Centralized analyses to confirm measurements obtained by different raters or sites.

What is the recommendation for biomarker development studies?

A priori designed large-scale multisite studies with a coordinated analysis plan including independent validation rather than post hoc sharing of data sets.

How does molecular PET imaging work?

It uses radiotracers to image specific targets in the brain.

What data can be obtained from molecular PET imaging?

Ssingle static snapshots of tracer distribution to sequential dynamic images recording kinetic profile of the tracer over a course of hours.

What is required for comprehensive mathematical models of imaging data in PET studies?

Drawing of blood samples from the subject to estimate the radioactivity that relates only to the parent radiotracer.

What is a key prerequisite for bloodless radiotracer methods?

The presence of a reference brain region that is devoid of receptors or other targets of interest which serves as a surrogate measure of radiotracer availability.

What does structural MRI provide?

An anatomical image that delineates different tissues (for example gray matter white matter and cerebrospinal fluid) and brain structures.

What does functional MRI measure?

Fluctuations in blood flow or oxygen level at rest or during a challenge (cognitive for example a memory test; or otherwise for example a drug challenge).

Define Sensitivity (true positive rate).

Refers to the proportion of individuals who test positive among those who have the outcome of interest (i.e. test outcome).

Define Specificity (true negative rate).

Refers to the proportion of individuals who test negative among those who do not have the outcome of interest (i.e. test outcome).

Define Positive Predictive Value (PPV).

Refers to the proportion of individuals who have the outcome of interest among those who tested positive (i.e. outcome test).

Define Negative Predictive Value (NPV).

Refers to the proportion of individuals who do not have the outcome of interest among those who tested negative.

What do internal validity, external validity and reliability refer to in the context of a study?

Internal validity refers to the ability to claim that the measure of interest in a study measures the intended feature in an unbiased way and without the influence of confounding third variables. External validity refers to the ability to extrapolate the results of a study to the general population of interest. Reliability refers to the consistency of a measure.

What have new initiatives of collaboration across academia and the pharmaceutical industry emphasized?

The development of reliable fMRI paradigms.

What is the approximate cost of MRI and PET scans?

An MRI scan costs around $600 per hour in academic centers and might be $1000 per hour in commercial centers in the United States of America. PET scans range from $3000 to $5000 per scan including radiotracer production.

What is a key consideration when evaluating biomarkers according to the text?

Cost effectiveness, determined by the clinical usefulness of the biomarker in avoiding additional expenses related to misdiagnosis unnecessary procedures or hospitalizations and other disease-related burden.

According to the text what limits the transition of neural abnormalities into true biomarkers?

The majority of clinical neuroimaging reports of neural abnormalities in clinical populations do not assess predictive value. Thus very few of the replicable abnormalities in psychiatric conditions can be regarded as actual biomarkers with potential clinical utility.

What neural abnormality has been reported in patients with MDD according to the text?

An average thinning of the cortical mantle in the prefrontal cortex which is associated with decision-making, self-control and other higher-order cognitive functions has been reported in adult patients with MDD compared to healthy individuals.

What evidence from meta-analyses of patients with schizophrenia supports a pathological process?

Pathological increase in dopamine storage and release capacity in presynaptic dopamine neurons which is correlated with the severity of psychotic symptoms.

What potential approach is illustrated for screening patients who could benefit from drugs that target the dopaminergic system?

Examining responders in comparison to nonresponders in the treatment of psychotic symptoms.

What replicated finding from patients with schizophrenia could potentially serve as an indicator of risk?

An increase in blood volume in the cornus ammonis region 1 CA1 region of the hippocampus.

What has been linked to treatment resistance in MDD?

Increased blood flow in the subgenual anterior cingulate.

What is reduced in patients with drug addiction compared to healthy individuals?

Dopamine-receptor availability in the striatum and gray matter volume in the ventromedial prefrontal cortex.

What do patients with obsessive-compulsive disorder (OCD) consistently show?

Increased volume of the striatum.

What do patients with anxiety disorders display?

Increased hemodynamic responsiveness of the amygdala to negative emotional stimuli.

What do patients with post-traumatic stress disorder show?

A specific decrease of activity in various prefrontal regions associated with the regulation of emotion.

What is an example of how structural MRI scans could be used in treating patients with OCD?

It can be used to decide whether to initiate pharmacotherapy with fluvoxamine vs cognitive- behavioural therapy as a first line of treatment.

What is a crucial first step in developing clinically useful neuroimaging biomarkers in psychiatry?

Defining a clinically relevant question that if addressed could potentially lead to improvements in patients long-term functioning and quality of life.

What did a landmark MRI study aim to predict?

The longitudinal clinical outcome in patients at high clinical risk for psychosis.

Does clinical relevance of biomarkers require respecting current diagnostic boundaries?

It doesn't require respecting current diagnostic boundaries especially when focusing on clinical outcome and treatment stratification.

What do biomarkers need to demonstrate to have potential clinical utility?

Useful information beyond routinely collected clinical and sociodemographic data to have potential clinical utility.

What did the ADHD-200 Global Competition demonstrate?

That personal characteristics outperformed imaging data in diagnostic classification of ADHD.

On what phenotypes should biomarkers operate?

Brain-based phenotypes directly associated with the physiological mechanisms of interest rather than on epiphenomenal consequences.

Why might a biomarker based on lithium treatment effects be problematic?

It may be equivocal for differential diagnosis in untreated patients.

What is required to validate a biomarker externally?

Demonstrating sufficiently high predictive value for clinical utility beyond statistical significance.

What does a significant difference in the distribution of a biological feature between health and disease imply?

It means that the probability of finding a difference of the observed size by chance is unlikely.

List the phases of biomarker development.

Phase I: Target identification

Phase II: Internal validation

Phase III: External validation

Phase IV: Demonstration of clinical utility.

Give examples of potential biomarkers.

Striatal dopamine-release capacity CA1, hippocampal CBV, Multivariate gray-matter markers.

What are the goals associated with biomarker development?

Prediction of conversion to disease in at-risk states.

Prediction of treatment response.

Differential diagnosis in ambiguous cases.

Ruling out confounding factors associated with outcome.

Demonstration of adequate NNANNT to improve clinical outcomes and quality of life.

Why is external cross-validation in an independent clinical sample necessary?

To avoid overfitting of the data on which the algorithm was trained and poor performance of this algorithm on new data such as data from new patients in clinical settings where the established algorithms need to be most accurate.

What determines the percentage of individuals who are actually ill or healthy when they are classified as such?

The amount of overlap between the groups is clinically more relevant because it determines the percentage of individuals who are actually ill or healthy when they are classified as suchthe positive and negative predictive value respectively.

What is the fourth step in biomarker development and what does it involve?

Longitudinal designs to establish the clinical utility of biomarkers. This includes confirming biomarker-based diagnoses and testing biomarker-based treatment selection in randomized controlled trials (RCTs).

What do NNT and NNA represent and how are they useful in the context of biomarker development?

NNT (number needed to treat) and NNA (number needed to assess) represent the number of individuals that need to undergo a certain procedure to benefit one individual. They are useful in synthesizing the potential utility of a biomarker.

What is required even after a clinically useful biomarker makes its way into real-world clinical settings?

Establishing the utility and cost-effectiveness of biomarkers. These studies should demonstrate a reduction in morbidity and improvement in quality of life for the general population.

What would the arrival of neuroimaging-based biomarkers for psychiatric disorders represent?

A historic paradigm shift in the biomedical sciences.

Which organizations recognize the need for biomarkers that predict clinical response or the emergence of side effects in drug trials?

The Food and Drug Administration (FDA) and the European Medical Agency (EMA)

What is needed to support the sheer scale of biomarker development?

Collaborative efforts across research sites and support by appropriate funding mechanisms designed a priori for this purpose.

What are the PPV and NPV values when Cohen's d is 2 and Prevalence is 25?

PPV is 0.64 and NPV is 0.93.

What are the PPV and NPV values when Cohen's d is 2 and Prevalence is 50?

PPV is 0.83 and NPV is 0.84.

What are the PPV and NPV values when Cohen's d is 1 and Prevalence is 50?

PPV is 0.71 and NPV is 0.74.

According to the text what should biomarker development employ?

Cost-effective platform that strikes a balance between hypothesis-driven development aimed at exploiting well-replicated imaging phenotypes with the potential to result in useful biomarkers and purely data-driven but nonetheless powerful approaches aimed at blindly exploring multimodal data sets.