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Initial Proposed claim:

  • Protocol template by UPICT (Uniform Protocols in Clinical Trials) UPICT Template

Initial Claim Sentence: Goal is to investigate the technical feasibility of creating a method for validating/optimizing design parameters of stimulus paradigms used in single-subject BOLD studies.

Discussion surrounding initial Claim sentence: To create a method for validating/optimizing design parameters of stimulus paradigms used in single-subject BOLD studies.

Objective: Characterize the robustness of signal change measurements in brain tissue that will lead to an understanding of the minimal threshold required to classify MR signal change in eloquent brain tissue as medically meaningful surrogate(s) for changes in brain activity.

Discussion notes from E. DeYoe:

To establish a context for the claim(s) that QIBA will address, we could propose an overall claim that would seem to be clinically relevant such as:

Claim 1: fMRI brain activation is a valid indicator (biomarker) of brain function in individual patients.

For specific paradigms this might be cast as:

Claim 2: fMRI activation within brain area X produced by paradigm Y is a valid indicator of the function of area X. (which for presurgical mapping could be further restricted to mean that excision or damage of the area would produce a neurological deficit.)

However, the focus of the QIBA group might be more restricted: Specifying specific measures (eg readouts) that could be used to address the preceding claims and establishing the characteristics of those measures.

Claim 3: For specific fMRI paradigms, the following measures of the BOLD signal can be used to determine if Claim 2 is true (How the measures are used to do this must also be specified for each paradigm).

  • (1) The intensity of task relative to baseline with a statistical parameter such as F or T (and its p value)
  • (2) The temporal correlation of the signal with the task timing (eg block design, event related, phase mapped).
  • (3) The spatial pattern of activation (density, clustering) and proximity to a site of pathology or proposed resection margin).
  • (4) Paradigm-specific indices derived from the BOLD signals.

For Claims 2 and 3 to be true, certain conditions or criteria must be met:

  • a. The scanner, and all associated peripherals are operating properly and this can be verified
  • b. The nature of the behavioral task is appropriate to activate the brain area(s) of interest. (This includes appropriate selection of a “baseline” condition against which the activation is detected.)
  • c. The parametric design of the fMRI task and the selection of scanner pulse sequence and parameters are appropriate and, preferably optimal.
  • d. The patient performs the behavioral task adequately and this can be verified. (This includes monitoring behavioral “state” variables such as attention and alertness.)
  • e. A valid computational method exists to obtain the various measures of the BOLD response from voxel signals and determine their statistical significance. (This means understanding the statistical sampling distributions of each BOLD measure and thus their reproducibility.)
  • f. Statistical acceptance criteria can be established that ensure that Claim 2 is valid at a specified level of probability.
  • g. The BOLD hemodynamic mechanism within the brain region of interest is not compromised (eg. there is no neurovascular uncoupling.)

Additional comments: Ultimately for surgical planning/guidance Claim 2 can be interpreted farther still to mean: If brain area X is to be surgically removed or compromised, does the fMRI activation predict whether a corresponding neurological deficit will occur? This is probably beyond the scope of what the QIBA group wants to address? Rather, we might focus primarily on conditions b-e listed above and assume that conditions a,f,g are met. Condition f is a sticky one because from a clinical perspective it not simply sufficient to say that a BOLD signal is statistically different from the baseline since this does not necessarily indicate that the associate brain region is functioning normally. However, our goal may be just to ensure that a statistical measure is mathematically accurate given the statistics of the task and baseline conditions.

As discussed in the recent phone conference there are several “levels” of technological and neurological issues that should be clearly differentiated. QIBA may only want to address some of these:

  • Level A. fMRI measurement and paradigm technology
  • Level B. Paradigm design and appropriateness for activating particular brain regions
  • Level C. The contribution of particular brain regions to specific behavioral or mental functions. This includes recognition that a given area may contribute to more than one behavior or mental function.
  • Level D. Clinical interpretation of A-C relative to a particular patient’s pathology, treatment choices, and potential outcomes (eg amelioration of pathology and quality of life).

It may only be appropriate for the QIBA group to address A and B?

An alternate way to cast the QIBA specific claims would be to focus on establishing the criteria for evaluating a particular paradigm and the BOLD measures derived from it.