1 SUPPLEMENTAL DIGITAL CONTENT

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SUPPLEMENTAL DIGITAL CONTENT

METHODS

This research was a Food and Drug Administration (FDA) approved investigational device exemption (IDE) study. All procedures were approved by the host institution’s Biomedical Sciences’

Institutional Review Board for the conduct of research with human participants. Participants and a significant other consented and assented to undergoing screening for eligibility. If a potential participant was found eligible in screening, a second consent/assent was required prior to study participation. All families were provided access to a patient advocate independent of the study team to assist in the decision to participate.

Inclusion/Exclusion criteria

Participants met the following criteria:

• Age 20-55 years at time of enrollment.

• Ability to follow simple commands as demonstrated by a score of 6 on the Glasgow Coma Scale motor component.

• Scores in the “Severe” range of the Glasgow Outcome Scale-Extended (GOS-E).¹

• Evidence of impaired cognitive functioning (5th percentile or less) in two or more domains (ie, attention, language, memory, spatial perception and executive functions) of the Neuropsychological Assessment Battery (NAB) Screening Module.²

• Medically and neurologically stable as determined by medical history, physical and neurological examination.

• Participant and proxy are willing to comply with all follow-up evaluations at the specified times.

• Participant is able to provide informed consent or has an appropriate legally authorized representative (LAR) to provide informed consent for the participant prior to enrollment in the study. All participants will be required to have designated an individual to provide support in decision-making and to act as a representative decision maker if the participant does not have (or loses) capacity to provide informed consent throughout the study.

• English must be the primary language of the participant.

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Participants were excluded if any of the following were present:

• Medical contraindications for general anesthesia, craniotomy, or deep brain stimulation (DBS) surgery.

• Severe cardiovascular, pulmonary, renal, liver, hematological disease, severe coagulopathy, acute infectious process.

• Evidence of substance (alcohol or other drug) abuse or dependence during the previous 12 months (DSM-IV Criteria).³

• Current diagnosis of major depressive disorder with recurrent episodes (DSM-IV criteria).³

• Condition requiring diathermy after DBS implantation.

• Participation in another FDA device or medication trial that would interfere with the current study.

• Current participation in the following rehabilitation services: physical therapy,

occupational therapy, speech therapy, cognitive remediation or psychological therapy.

• Participants with >50% destruction and/or damage to the target region as determined by Magnetic Resonance Imaging (MRI).

• Co-morbid conditions that would interfere with study activities or response to treatment, including:

o Neoplasm with life expectancy < 5 years.

o Severe Chronic pulmonary disease.

o Intractable seizure disorders.

o Local, systemic acute or chronic infectious illness.

o Life threatening cardiac arrhythmias.

o Severe collagen vascular disorder.

o Kidney failure or other major organ systems failures.

• Other active neurological disease/processes (eg, brain tumor or multiple sclerosis).

Instrumentation

Functional Independence measures

The Mayo-Portland Adaptability Inventory-4 (MPAI-4)⁴ total raw score was the primary outcome measure for this study, and was obtained as part of both the assessment and monitoring protocols. The MPAI-4 was developed for measuring progress in rehabilitation following TBI. The instrument consists of 35 items rated according to degree of interference with everyday activities and includes three

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subscales: Ability Index (cognitive, sensory, motor abilities), Adjustment Index (mood and behavior), and Participation Index (self-care and community living). Versions are available for completion by persons with TBI, caregivers, and clinicians. The caregiver version was used in the current study. Now in its fourth revision, the MPAI-4 has highly developed and well documented psychometric properties. In addition to meeting criteria of classical test theory (reliability, criterion-related validity and construct validity) the scale was developed and revised using Rasch, or rating scale, analysis.⁴ Based on the Standard Error of Measurement for a large, untreated population of persons with severe TBI, the

minimally important difference was estimated for the current study to be 3.4 units. Previous studies using the MPAI-4 have found clinical differences more than 3 times larger than the SEM. Patients many years post-injury with initial, severe TBI had MPAI-4 scores, on average, 12 points worse than those with mild injuries; patients with initial moderate injuries differed by 7 points.⁵ In a study of patients 5 months after injury, severe TBI patients with and without growth hormone deficiency differed by 11 points on the MPAI-4.⁶

The Functional Independence Measure (FIM^TM)⁷ was administered as part of the assessment protocol. The instrument consists of 18 items rated on the degree to which people can independently perform tasks in six areas: self-care, toileting, transfers, locomotion, communication and social cognition.

Measurement properties of the FIM have been reported extensively^7-9 Precision (the ability of the

instrument to detect meaningful change in level of function during rehabilitation) has been observed to be high.^8,10,11 The FIM has clinically appropriate validity and inter-rater agreement.^7,8 In a Rasch Analysis of the FIM, two separate domains of items were defined: the motor domain consisting of 13 items and the cognitive domain consisting of 5 items.¹⁰ In its use in TBI, the FIM has been found to be highly predictive of minutes of assistance needed (83% accuracy), supervision required (82% accuracy), and the need for either type of assistance (78% accuracy).⁸

Cognitive measures

The Wechsler Adult Intelligence Scale, III ¹² Digit Symbol, Symbol Search, Letter-Number Sequencing, and Digit Span subtests were administered as part of the assessment protocol. The Wechsler family of scales was first developed in 1955, and has since undergone multiple revisions with new normative samples. The psychometric properties of the WAIS-III are well-established and accepted in the field.¹³

The Trailmaking Test, Forms A and B (TMT-A, TMT-B)¹⁴ was administered during the

assessment protocol. The instrument requires the participant to connect circles with number and letters in sequence and is purported to measure visual scanning and visual-spatial sequencing, attention,

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psychomotor speed and mental flexibility. Test-retest reliability have been established, with mixed findings in regard to practice effects; multiple studies have confirmed construct validity.¹³

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)¹⁵ was originally developed to measure change associated with dementia. It provides measures of attention, immediate and delayed memory, language and visual-spatial skills. A total score and five subscale indices can be calculated. The RBANS has been used successfully in studies of persons with TBI^16,17 and has been found to be sensitive to change due to interventions.¹⁷ In a study of reliability and validity with persons with moderate-severe TBI, internal consistency was found to be good for the total score (Cronbach’s alpha=.84) and convergent validity with comparable neuropsychological measures.¹⁸ The RBANS was administered more frequently than other measures, so for this measure we used the scores in a slightly different manner. In order to reduce test-retest effects, three different versions of the form were used. While purported to be equivalent, the forms appeared to present varied levels of difficulty with some subtests. Therefore, the average of the participant’s total standard score for that form was subtracted from the total standard score for each administration. With this done, we then averaged the scores across all of the administrations in a particular study phase for each participant.

Decision-making measures

Decision-making or self-regulation involves the ability to make choices and engage in behaviors that are consistent with one’s long-term goals. The Iowa Gambling Task (IGT)¹⁹ was used to obtain an overall measure of decision-making or self-regulation, and was administered as part of the assessment protocol. The Iowa Gambling Task assesses the combined influence of the various components of decision-making (reversal learning, delay discounting, risk-taking). The IGT has been used with multiple clinical populations,^20,21 including TBI.^22,23 The measure has been studied in relationship to neuroimaging findings.^22,24,25 For the current study, both the conventional scoring metric as well as a recently developed alternative that has been found to be a better fit with neuroimaging findings²⁶ were utilized.

The Lane Risk-taking Task, administered as part of the assessment and monitoring protocols, requires the participant to choose between receiving certain, smaller monetary gains (safe response) versus an option that could lead to larger gains or losses (risky response). The paradigm has been used to study the effects of alcohol on risk-taking in conjunction with neuroimaging findings.^27,28 Deliberation prior to the selection of a risky response has been found to be associated with activation in the nucleus accumbens, medial frontal cortex, occipital cortex and caudate, while deliberation prior to the selection of a safe response is associated with activation in the superior and middle temporal gyrus and the inferior frontal cortex.²⁹

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Composite scores

The Functional Composite score combined the MPAI-4 with the Functional Independence Measure (FIM) Motor and Cognitive subscales. The Cognitive Composite score used the Total from the RBANS, the standard scores for the WAIS-III. Digit Symbol, Symbol Search, Letter-Number

Sequencing, and Digit Span subtests, and the Trailmaking A and B T scores. The Decision-making Composite score was composed of 3 scores: D-A and CD-AB from the first 100 trials of the Iowa Gambling Task (IGT) and total percent non-risky choices Lane Risk-Taking Task. Scores for each measure were individually mean centered over the 5 phases within participants and then normalized by the standard deviation for that measure across participants. The composites were then constructed as the average of the centered, normalized component measures at each time point.

Neuroimaging and processing

Low dose 18F-FDG (170±19.MBq / 4.6±0.5 mCi) brain PET/CT scans were performed on a Gemini TF 64 Astonish system (Philips Healthcare) during each of the five phases of assessment. Patients fasted at least 4 hours with no more than 180mg/dL glucose levels prior to the PET/CT imaging. A continuous list mode acquisition was performed starting with FDG-administration and 15 min volume sets were reconstructed for analysis. The data set from 45-60 min was used for quantitative assessment.

An attempt was made during PET/CT acquisition to minimize potential head movement of patients and improve image quality and a quality assurance performed to insure that no motion induced miss

registration is included in the reconstructed list mode data stream. PET image were reconstructed using a 3D-Ramala iterative approach with 2mm slice thickness, 128x128 matrix and CT-based attenuation correction. Imaging data were de-identified and stored on dedicated Intellispace Portal System (ISP, Philips Healthcare) for further post-processing.

MRI Imaging was performed on an Achieva 32 channel receive, 2 channel multi-transmit 3T system (Philips Healthcare). The T1 weighted high resolution anatomical MRI was acquired using Turbo Field Echo sequence. Processing steps were carried out with AFNI and FSL.^30,31 Baseline structural MRIs were sequentially co-registered using FSL’s nonlinear registration tool (FNIRT) to create a group

template. DICOM PET/CT data were converted to NIFTI files for integration with MRI data. PET images from each of the five imaging time points were registered to each participant’s baseline MRI and then transformed to the group template. PET images were mean centered individually based on an ROI in the ventricles. Voxels with a maximum intensity more than five times greater than their minimum intensity were excluded from further analysis in order to remove voxels that were not in viable brain tissue in all participants. Images were z-scored based on the activation in the remaining voxels. Due to this

normalization, all results examine relative, as opposed to absolute, changes in brain activity. Analyses

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were conducted in a group template space at 4mm resolution, then up-sampled and projected onto participant initial pre-surgical anatomical MRI for display. Axial slices for Figure 3A-C were generated with MRIcroGL.³² Three-dimensional surface reconstructions of participant initial pre-surgical MRI were generated with Freesurfer³³and images were generated using pycortex.³⁴

ANALYSIS

For the primary outcome measure and each composite we used repeated measures ANOVA with post-hoc pairwise t-tests corrected for multiple comparisons via Holm’s method (Holm, 1979) to

determine if the measure significantly changed over the course of the study. We used Linear Mixed Effects Regression with Permutation based Hypothesis Testing (LMER-PHD, see supplemental methods) to test the hypotheses that relative neural activity across participants is related to composite scores.

Linear mixed effects regression (LMER) is a widely used multilevel parametric analysis method.^35-37 The key advantage of LMER is that it simultaneously accounts for effects within and between participants. In our analyses we sought to correlate behavioral and functional assessments with neuroimaging results. This application raised three challenges for LMER analysis: outlier effects, small sample size, and multiple comparisons. Our innovation was to pair LMER with threshold free cluster enhancement (TFCE)³⁸ and a nonparametric hypothesis test, which we termed Permutation Hypothesis Discrimination (PHD). By randomly reordering the neuroimaging measurements within participants, we were able to create datasets in which the neuroimaging data had no consistent, across-participant relationship with the variables to which it was being compared. We then ran LMER followed by spatial TFCE of the LMER t-stat on each element (voxel) of the neuroimaging data in each of 500 permutations, producing a null distribution of cluster-enhanced images comprising the results expected by chance that we could compare to our cluster-enhanced true, unshuffled data. For any given threshold value, we could then calculate the p-value of our true results as the proportion images in our null data with more voxels surpassing this threshold than surpass the threshold in our true result. Because our null distribution draws from the same data as the true data, our estimates of significance and uncertainty account for both outlier effects and sample size. LMER-PHD analyses were completed with in-house software written in Python and R.^39,40

For the present analyses we used LMER-PHD to determine, at each voxel in the PET data, if there was an across-participants relationship between variation in relative PET activity and each of the composite. The slope and y-intercept of the relationship was allowed to vary by participant. The LMER model implementing this analysis is as follows: PET intensity ~ Measure + (1 | Participant) + ((Measure- 1) | Participant) where Measure is a composite score. As explained above, the LMER model was run at each voxel in each of 500 permutations in addition to the true data. TFCE was then run on each LMER t-

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stat from each of the 500 permutations and the true data. The p-value of thresholds set at each value in the true result was then determined. The p-value of a threshold was calculated as the proportion of

permutations with more voxels above threshold than the number of voxels above threshold in the true data. Measures with a threshold corresponding to a p-value of less than 0.05 were taken to be significant.

For these measures the TFCE threshold resulting in a p-value closest to 0.05 without being greater was used to generate a mask. This mask was applied to the LMER t-stat image from the true data. We applied a secondary threshold of t >= 2.5 to the masked t-stat images to identify significant regions. These images were up sampled to 1 mm for display.

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TABLE 1. Contact 0 locations.

Left Right

Participant X Y Z X Y Z

1 9 mm 3 mm 2 mm 10 mm 4 mm 4 mm

2 12 mm 4 mm 5 mm 11 mm 4 mm 4 mm

3 9 mm 5 mm 4 mm 9 mm 4 mm 3 mm

4 10 mm 4 mm 5 mm 8 mm 3 mm 4 mm

Coordinates are rounded to the nearest millimeter lateral from the midline (X) and anterior (Y) with respect to the anterior commissure, and ventral (Z) below the anterior commissure.

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TABLE 2. Stimulation settings.

Right Left

Participant

Study

Phase Anode Cathode

Pulse Width (µs)

Frequency (Hz)

Amplitude

(V) Anode Cathode

Pulse Width (µs)

Frequency (Hz)

Amplitude (V)

1 3 and 4 1 0,2 150 80 6 1 0,2 150 80 6

1 5 1 0,2 150 80 6 1 0,2 150 80 6

1 6 1 0,2 150 80 8 1 0,2 150 80 7

2 3 and 4 0,3 1,2 90 30 8 0,3 1,2 90 30 8

2 5 0,3 1,2 90 20 8 0,3 1,2 90 30 8

2 6 0,3 1,2 120 120 6 0,3 1,2 90 150 7

3, program 1 3 and 4 1 0 150 90 4 2 3 210 210 4

3, program 2 3 and 4 2 1 210 90 4 2 3 210 210 4

3, program 1 5 1 0 150 90 4 2 1 210 90 4

3, program 2 5 2 1 90 90 4 2 3 90 180 4

3, program 1 6 1 0 90 90 4 1 2 120 200 7

3, program 2 6 2 1 90 90 8 1 2 120 200 7

4 3 and 4 2 0,1,3 150 210 4 2 0,1 150 210 4

4 5 2 0,1,3 90 210 4 2 0,1 90 190 4

4 6 2 0,1,3 90 210 5 2 0,1 90 190 5

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TABLE 3. MPAI-4 raw scores.

Participant Study Phase

MPAI-4 Total

MPAI-4 Ability

MPAI-4 Adjust-

ment

MPAI-4 Partici-

pation

1 Pre-Surgical Baseline 55 19 20 26

1 Post-Surgical Baseline 47 17 14 25

1 Stimulation 44 16 13 24

1 Rehabilitation 43 15 13 24

1 Follow-up 9 months 48 14 19 23

1 Follow-up 2 Years 39 13 11 23

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FIGURE 1. MPAI-4 raw scores by study phase with response compared to presurgical baseline shown.

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TABLE 4. Scores comprising the Functional Composite Score.

Participant Study Phase MPAI-4

FIM- Cognitive

FIM Motor

1 Pre-Surgical Baseline 55 22 64

1 Post-Surgical Baseline 47 22 64

1 Stimulation 44 22 67

1 Rehabilitation 43 26 68

1 Follow-up 9 months 48 26 68

1 Follow-up 2 Years 39 27 71

2 Rehabilitation 65 -- --

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TABLE 5. Scores comprising the Cognitive Composite Score.

Participant Study Phase RBANS Digit Span Letter-

Number Sequencing

Digit-Symbol Symbol

Search Trails A-T Trails B-T

1 Pre-Surgical Baseline -.37 5 2 2 2 16 4

1 Post-Surgical Baseline -.20 4 4 3 2 16 4

1 Stimulation -.21 5 3 2 2 21 5

1 Rehabilitation .12 5 5 3 2 52 5

1 Follow-up 9 months .24 5 2 2 2 26 23

1 Follow-up 2 years .66 4 3 2 2 13 5

2 Stimulation .01 7 4 2 1 8 6

2 Follow-up 9 months .03 4 1 3 1 8 6

2 Follow-up 2 years -.10 5 1 2 1 9 7

3 Stimulation .17 9 7 4 4 36 45

3 Follow-up 9 months .43 8 7 4 6 32 22

3 Follow-up 2 years -70 8 9 3 5 37 36

4 Stimulation -.30 5 1 3 4 19 8

4 Follow-up 9 months .42 4 2 3 1 19 8

4 Follow-up 2 years .11 5 2 2 3 11 9

Digit Span, Letter-Number Sequencing, Digit-Symbol, and Symbols Search are tasks from the Wechsler Adult intelligence scales––standard scores are presented. The RBANS is the average z score for the phase.

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TABLE 6. Scores for Decision-making Composite Score.

Participant Study Phase Iowa Gambling Task DA 1-100

Iowa Gambling Task

CDAB 1-100 Percent Non-Risky

1 Pre-Surgical Baseline 2 -2 20

1 Stimulation -1 -4 4

1 Follow-up 2 years 0 0 20

2 Pre-Surgical Baseline -1 -10 100

2 Post-Surgical Baseline -5 -26 72

2 Stimulation -14 -42 92

2 Rehabilitation 5 -4 28

2 Follow-up 9 months -26 -72 100

2 Follow-up 2 years -- -- 12

3 Stimulation 3 -24 56

3 Rehabilitation 13 -10 64

3 Follow-up 2 years -6 -28 32

4 Pre-Surgical Baseline 5 -10 88

4 Follow-up 2 years 7 12 100

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FIGURE 2. Decision-Making Composite: The trajectory of the normalized Decision-Making

Composite scores. Participants 2 and 4 showed increased Decision-making Composite scores

across phases.

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FIGURE 3. Normalized PET activity by study phase. For peak voxels from four areas of high

correspondence between cognitive composite score and normalized PET activity.

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● ●

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● ●

●

● ●

●

● ●

●

● ●

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Participant 1 Participant 2

Participant 3 Participant 4

2 3 4 5

2 4 6 2 4 6

Study Phase

Normalized PET

Region

●

Left OFC Left IC Left MiFG Left IFG

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