The purpose of this study was to evaluate the effect of 4-week SPN-810 treatment on brain functioning in patients aged 8-12 years with ADHD and associated feature of impulsive aggression (IA). This was achieved using functional magnetic resonance imaging (fMRI) in conjunction with the point subtraction aggression paradigm (PSAP) Task, a behavioral aggression paradigm in which subjects are provoked by having money indirectly taken from them by a fictitious opponent, simulating an aggression response.
Approximately 30 subjects aged 8-12 diagnosed with ADHD and associated feature of IA were recruited in this study. The PSAP is a behavioral aggression test used to evaluate behavioral response related to impulsive aggression. The task was combined with functional MRI to evaluate the change in brain activity measured as BOLD signal (blood oxygenation level-dependent) from baseline to the end of the treatment with SPN-810. The level of neurotransmitters Glutamate and GABA were also measured using magnetic resonance spectroscopy (MRS). Additionally, the improvement and severity in impulsive aggression behaviors were assessed using validated scales.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
7
Neural brain activity measured by fMRI
Glutamate and GABA levels measured by MRS
Aggression score measured by the PSAP task
Treatment of SPN-810 (36 mg) on neuronal brain activity, GABA and Glutamate levels and on the aggression score
Treatment of placebo on neuronal brain activity, GABA and Glutamate levels and on the aggression score
Meridien Research aka Florida Clinical Research Center, LLC
Lakeland, Florida, United States
Florida Clinical Research Center, LLC.
Maitland, Florida, United States
University of South Florida- Dept. of Psychiatry and Neurosciences
Tampa, Florida, United States
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task
The primary endpoint was the aggression-related change in the whole brain in BOLD signal fMRI contrast in response to the PSAP task. BOLD fMRI contrast (neural activation) investigates brain activity by measuring the change in blood oxygenation. Change in brain activity was measured by a change in BOLD response in brain regions during the aggressive response relative to the monetary response, where the aggression was defined as the number of Option 2 presses (aggressive response) divided by the total number of button presses and the number of provocations. Change of aggression-related MRI signal was acquired at baseline and 4 weeks after SPN-810 treatment. A positive number represents an increase in activity. Region of interest is described by the location of the peak value and described by Montreal Neurological Institute (MNI) X, Y, Z coordinates. Data represent the post-treatment minus baseline change in BOLD contrast Aggressive Response\> Monetary Response.
Time frame: Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.
Provocation Event - Related Change in the Whole Brain in BOLD Signal fMRI Contrast in Response to the PSAP Task
BOLD (blood oxygenation level-dependent) fMRI contrast (neural activation) investigates brain activity by measuring the change in blood oxygenation. It was collected during the PSAP behavioral task while playing the game: the participants play a computer game in which they can steal points (simulating an aggressive behavior) or have points stolen by the opponent (provocation event) by pressing Option 1, 2 or 3 on a keypad a set number of times to achieve a specific outcome. A positive number represents an increase in activity. The region of interest is described by the location of the peak value within that cluster and described by Montreal Neurological Institute (MNI) X, Y, and Z coordinates. Data represent the post-treatment minus baseline change in BOLD contrast Provocation Event \>Monetary Response.
Time frame: Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.
Effect of SPN-810 on the Aggressions Score
The Point Subtraction Aggression Paradigm (PSAP) is a behavioral aggression paradigm consisting of a computer game in which each participant plays against a computer to earn points. The subject can steal points (i.e., aggressive behavior) or have points stolen by the opponent (i.e., provocation). The subject can press 1 of 3 buttons on a keypad a set number of times. By pressing the button for Option 1, 100 times, the subject will earn a point; pressing the button for Option 2, 20 consecutive times is the "aggression" action that results in stealing a point from the opponent; pressing Option 3, 20 times protects the subject from the opponent's attempt to steal points (i.e., money). The aggression score is averaged across two sessions and calculated as the number of Option 2 button presses divided by the sum of total button presses and the number of provocation events received, with a range minimum = 1, maximum = 143. The higher scores reflect increased aggression.
Time frame: Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.
Effect of SPN-810 on GABA and Glutamate Levels Using Magnetic Resonance Spectroscopy (MRS)
GABA and Glutamate concentrations (mM) were measured in the anterior cingulate cortex using magnetic resonance spectroscopy (MRS). Data represent the change from Baseline (Visit 2) to Visit 5.
Time frame: Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.
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