Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/48—Other medical applications
  • A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
  • A61B5/242—Detecting biomagnetic fields, e.g. magnetic fields produced by bioelectric currents
  • A61B5/245—Detecting biomagnetic fields, e.g. magnetic fields produced by bioelectric currents specially adapted for magnetoencephalographic [MEG] signals
  • A61B5/246—Detecting biomagnetic fields, e.g. magnetic fields produced by bioelectric currents specially adapted for magnetoencephalographic [MEG] signals using evoked responses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
  • A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system

Definitions

• the present invention relates to the field of diagnosing neurological disorders, particularly autism spectral disorders.
• MEG Magnetoencephalography
• STG superior temporal gyrus
• ASD Autism Spectrum Disorders
• ITC inter-trial coherence
• the method comprises measuring brain activity in the subject by magnetoencephalography after administering a stimulus (e.g., an audio stimulus) to the subject.
• a stimulus e.g., an audio stimulus
• the 50 and/or 100 ms latency is measured.
• the brain activity e.g., latency
• An increase in the delay of the response in the subject compared to a normal subject indicates that the subject has the neurological disorder.
• the stimulus elicited activity in the gamma frequency is measured (e.g., the inter trial coherence or steady state gamma power is measured).
• a decrease in the stimulus elicited activity in the gamma frequency in the subject compared to a normal subject indicates that the subject has the neurological disorder.
• the method comprises administering a compound to a subject and subsequently measuring brain activity in the subject by magnetoencephalography after administering a stimulus (e.g., an audio stimulus) to the subject.
• a stimulus e.g., an audio stimulus
• the brain activity e.g., latency
• a modulation in the brain activity after administration of the compound indicates the compound's activity against the neurological disorder. For example, a decrease in the delay in the 50 and/or 100 ms response compared to that observed prior to administration of the compound
• baseline indicates that the compound is therapeutic against the neurological disorder.
• an increase in the stimulus elicited activity in the gamma frequency band compared to that observed prior to administration of the compound (baseline) indicates that the compound is therapeutic against the neurological disorder.
• Figure 1 shows evoked activity and family wise-corrected p-value plots comparing TD and ASD for each frequency.
• TD > ASD differences are shown in blue, ASD > TD differences in red.
• Arrows show examples of where greater evoked gamma activity was observed in TD than ASD.
• Figure 2 shows ITC activity and familywise-corrected p-value plots comparing TD and ASD for each frequency.
• ITC values* were log transformed to highlight activity at higher frequencies.
• TD > ASD differences are shown in blue, ASD > TD differences in red. Red arrows show examples of where greater ITC gamma activity was observed in TD than ASD
• Figure 3 provides a scatterplot of CELF-4 Core Language Index scores (x axis) and right STG pre-stimulus gamma activity (y axis; 30 to 50Hz) in individuals with ASD.
• x axis CELF-4 Core Language Index scores
• y axis right STG pre-stimulus gamma activity
• Figure 4 provides scatterplots of age (x axis) and pre-stimulus total power (average of 4 to 80 Hz activity).
• TD top row
• ASD bottom row
• increased pre-stimulus activity predicted a younger age. Males are shown in blue and females in pink.
• Figure 5 provides graphs of Ml 00 latency in autism in response to STX209, showing baseline and post-treatment.
• Figure 6 shows the MEG measures of inter trial coherence in autism response to STX209.
• Figure 7 shows the MEG measures of steady state gamma in autism response to STX209.
• Increased pre-stimulus activity in ASD likely demonstrates a fundamental signal-to-noise deficit in individuals with ASD, with elevations in oscillatory activity suggesting an inability to maintain an appropriate 'neural tone' and an inability to rapidly return to a resting state prior to the next stimulus.
• pre-stimulus activity predicted Ml 00 latencies in both groups.
• Other findings also pointed to pre-stimulus activity as a measure warranting additional study: (1) higher 30 to 50Hz right hemisphere pre-stimulus activity (total power) was associated with lower CELF-4 Core Language Index scores, and (2) although age was associated with pre-stimulus measures, group differences in left hemisphere pre- stimulus activity (4 to 80 Hz) remained even after removing variance in pre-stimulus activity associated with age.
• post-stimulus gamma abnormalities in ASD likely indicate an abnormal excitatory/inhibitory balance in cortical microcircuits, with this imbalance perhaps indicative of an impairment in information processing during passive listening.
• the increase in theta to gamma pre-stimulus activity may be a more general feature of several neurodevelopmental disorders.
• increased pre-stimulus gamma has been reported in schizophrenia (Gandal et al. (2012)
• the Ml 00 responses were observed less often in the left than in the right hemisphere.
• 90% of the children with ASD had an observable right Ml 00 response
• 63% had an observable left Ml 00 response.
• Data from individuals with ASD with perhaps very abnormal auditory activity i.e., no identifiable M100 response
• left-hemisphere abnormalities in the present study may be greatly
• binaural auditory stimuli may also be used.
• the binaural auditory stimuli may allow for a more specific examination of the contributions of ipsilateral versus contralateral pathways to the observed STG auditory abnormalities.
• ASD-4 Core Language Index Deficits in synaptic integration in the auditory cortex may be associated with oscillatory abnormalities in ASD as well as patient symptoms. Increased pre-stimulus activity in ASD likely demonstrates a fundamental signal-to-noise deficit in individuals with ASD, with elevations in oscillatory activity suggesting an inability to maintain an appropriate 'neural tone' and an inability to rapidly return to a resting state prior to the next stimulus.
• ASD autism spectrum disorders
• the methodology of the instant invention addresses both of these issues and can thus be considered a family of measures suitable for use as "stratification biomarkers” and "early signals of efficacy.”
• MEG magnetoencephalography
• ITC inter-trial coherence
• the method comprises measuring brain activity using magnetoencephalography after a stimuli, particularly an audio stimuli (e.g., a simple or complex audio stimulus; e.g., an audio signal of about 100 to about 1000 Hz, particularly about 200 to about 700 Hz or about 300 to about 500 Hz).
• a stimuli particularly an audio stimuli (e.g., a simple or complex audio stimulus; e.g., an audio signal of about 100 to about 1000 Hz, particularly about 200 to about 700 Hz or about 300 to about 500 Hz).
• the 50 and/or 100 ms (latency) responses are measured, wherein a delay in the response compared to normal subjects indicates the subject has an autism spectrum disorder.
• the amount of delay may be correlated to the severity of the autism spectrum disorder.
• the stimulus elicited activity in the gamma frequency band (about 30 to about 50 Hz, particularly about 40 Hz) is measured, wherein a diminished inter-trial coherence (ITC) compared to normal subjects is indicative of autism spectrum disorder.
• ITC inter-trial coherence
• the severity in decrease may be correlated to the severity of the autism spectrum disorder.
• the subject and controls are age-matched.
• the method comprises administering a therapy (e.g., administering a compound and/or a non-pharmacological intervention) to the subject and performing the above magnetoencephalography methods, wherein a movement of the results from a baseline of the subject (i.e., before administration of the therapy (e.g., compound)) towards that of a normal subject indicates that the therapy (e.g., compound) is effective against the autism spectrum disorder.
• a therapy e.g., administering a compound and/or a non-pharmacological intervention
• the methods may further comprise performing the above magnetoencephalography methods above to establish a baseline prior to the administration of the therapy.
• Any kind of compound or molecule may be tested as a candidate therapeutic in the methods of the present invention, including, but not limited to, natural or synthetic chemical compounds (such as small molecule compounds), organic and inorganic compounds and molecules, and biological macromolecules (such as saccharide-, lipid-, peptide-, polypeptide- and nucleic acid- based compounds and molecules).
• a subject is a candidate for a therapy against a neurological disorder, particularly an autism spectrum disorder.
• the subject is a child (e.g., up to 18 years of age), particularly a young child (e.g., up to 3, 4, or 5 years of age).
• the method comprises administering a therapy (e.g., administering a compound and/or a non- pharmacological intervention) to the subject and performing the above
• the methods may further comprise performing the above magnetoencephalography methods above to establish a baseline prior to the administration of the therapy.
• the therapy may be an approved therapy for the neurological disorder or may be a candidate therapy for the neurological disorder.
• the instant methods can be used to determine if a patient is appropriate for inclusion in a therapy (e.g., drug) trial.
• Any kind of compound or molecule may be tested as a candidate therapeutic in the methods of the present invention, including, but not limited to, natural or synthetic chemical compounds (such as small molecule compounds), organic and inorganic compounds and molecules, and biological macromolecules (such as saccharide-, lipid-, peptide-, polypeptide- and nucleic acid-based compounds and molecules).
• natural or synthetic chemical compounds such as small molecule compounds
• organic and inorganic compounds and molecules such as small molecule compounds
• biological macromolecules such as saccharide-, lipid-, peptide-, polypeptide- and nucleic acid-based compounds and molecules.
• electrophysiological signatures serve as biomarkers of neurodevelopmental disorders of neuronal abnormalities in conditions such as autism spectrum disorder (ASD), rendering them detectable very early in development.
• ASD autism spectrum disorder
• the magnetoencephalography (MEG) system may be optimized to detect brain activity from children ⁇ 6- to ⁇ 48-months-old. Accordingly, it is desirable to use an infant and/or child MEG system.
• An example of a whole-head infant and/or young child MEG system is Artemis 123 which is described in Roberts et al. (Frontiers Hum. Nuerosci. (2014) 8: 1-99).
• the method comprises using fractional or diffusion anisotropy (e.g., performing diffusion tensor imaging).
• an increase in axial diffusivity compared to normal subjects indicates the subject has an autism spectrum disorder.
• a slower rate of maturational decrease of radial diffusivity compared to normal subjects indicates the subject has an autism spectrum disorder.
• the term "subject” refers to an animal, particularly a mammal, particularly a human.
• a "child” refers to a human up to 18 years of age.
• the term “autism spectrum disorder” refers to a group of developmental disabilities that includes, without limitation: autism; Asperger syndrome; pervasive developmental disorder not otherwise specified (PDD-NOS or atypical autism); Rett syndrome; and childhood disintegrative disorder.
• An "autism spectrum disorder” typically refers to a disease or disorder that is characterized by varying degrees of (1) deficits in social interaction, (2) deficits in verbal and nonverbal communication, and (3) repetitive behaviors or interests.
• diagnosis refers to detecting and identifying a disease in a subject.
• the term may also encompass assessing, evaluating, and/or prognosing the disease status (progression, regression, stabilization, response to treatment, etc.) in a patient known to have the disease.
• the term “prognosis” refers to providing information regarding the impact of the presence of a disease on a subject's future health (e.g., expected morbidity or mortality, the likelihood of developing disease, and the severity of the disease). In other words, the term “prognosis” refers to providing a prediction of the probable course and outcome of the disease or the likelihood of recovery from the disease.
• small molecule refers to a substance or compound that has a relatively low molecular weight (e.g., less than 4,000, less than 2,000, particularly less than 1 kDa or 800 Da).
• small molecules are organic, but are not proteins, polypeptides, or nucleic acids, though they may be amino acids or dipeptides.
• Epochs 500ms pre-stimulus to 500ms post-stimulus were defined from the continuous recording. Eye-blink and heartbeat activity were corrected using procedures outlined in Roberts et al. (Autism Res. (2010) 3:8-18). Epochs with artifacts other than blinks or heartbeat were rejected by amplitude and gradient criteria (amplitude>1200fT/cm, gradients>800fT/cm/sample). Noncontaminated epochs were averaged according to stimulus type.
• Determination of the strength and latency of Ml 00 sources in the left and right STG was accomplished by applying a standard source model to transform each individual's raw MEG surface activity into brain space (MEG data co-registered to the Montreal Neurologic Institute (MNI) averaged brain) using a model with multiple sources (Scherg, M. (1990) Fundamentals of dipole source potential analysis, in Auditory evoked magnetic fields and electric potentials. Advances in audiology, M.H.G.L.R. Gandori, Editor. Karger: Basel, Switzerland, p. 40-69; Scherg et al. (1996) Electroencephalogr Clin Neurophysiol SuppL, 46: 127-37 ; Scherg et al.
• the source model was constructed by including (1) left and right STG dipole sources, and (2) nine fixed regional sources that model brain background activity and serve as probe sources for additional oscillatory activity.
• the eye-blink source vector derived for each participant was also included to remove eye-blink activity (Berg et al. (1994) Electroencephalogr Clin Neurophysiol, 90:229-41 ; Lins et al. (1993) Brain Topogr, 6:65-78).
• the final source model serves as a source montage for the raw MEG (Scherg et al. (1994)
• Time-frequency measures were computed from - 400 to 400ms relative to stimulus onset. For evoked activity, background activity at each frequency (average power -400 to -100ms) was calculated and subtracted as a function of frequency. In addition to evoked activity, for each time-frequency bin, a measure of phase-locking referred to as inter-trial coherence was computed as ⁇ w ere the sum is over all N trials, and 0(k) is the phase of the signal in the k th trial.
• time- frequency analyses were re-run removing females (there were not enough females in the ASD group to compute female-only analyses).
• region-of- interest analyses were run with age as a covariate to determine if the group differences remained after controlling for age (given that groups did not differ on age, the use of age as a covariate was appropriate).
• Inter-trial Coherence As shown in Figure 2, corrected clusters indicated decreased left- and right-hemisphere gamma ITC in the ASD versus the TD group from -50 to ⁇ 200ms (clusters) at 300, 500, and 1000 Hz (although the grand average plots suggest right gamma group differences at 200 Hz, this did not reach significance in this sample). ITC measures were more sensitive to low-frequency group differences than evoked measures. In particular, decreased low-frequency ITC in the ASD than TD group was observed from 50 ms onwards at all frequencies except 1000 Hz.
• ITC time-frequency analyses were re-run including only males.
• the pattern of findings was unchanged for left 300 Hz and marginally significant for right 300 Hz.
• Excluding males no group differences were resolved for left or right 500 Hz gamma activity.
• Pre-stimulus Oscillatory Activity Given that the four tones (i.e., 200, 300, 500, and 1000 Hz) were randomly presented, group pre-stimulus differences were assessed after averaging the trials for all tones (approximately 420 trials). The pre- stimulus measure was computed by time-frequency transforming each trial and then averaging (i.e., a pre-stimulus total power measure was computed). Table 1 shows that except for right STG high gamma, group differences were observed at all examined frequencies (i.e., theta, alpha, beta, low gamma, high gamma), with pre- stimulus power elevated in ASD.
• Figure 5 shows that the auditory Ml 00 latency is shortened post-treatment. Indeed, a reduction in 100 ms latency for 4 stimuli in both hemispheres was observed.
• Figures 6 and 7 demonstrate an elevation of gamma-band inter-trial coherence in both hemispheres.
• Figure 6 shows that no significant gamma ITC existed at baseline whereas gamma band ITC was restored after treatment.
• Figure 7 shows that steady state gamma power (elicited by AM tone, driven at 40Hz) is boosted post-treatment.
• WM white matter
• Diffusion tensor imaging allows indirect measurement of white matter maturation and of the microstructural properties of WM through fractional anisotropy (FA), a measure of the organization of water diffusion (Beaulieu, C. (2002) NMR Biomed., 15:435- 455; Harsan et al. (2006) J. Neurosci. Res. 83 :392-402).
• MEG magnetoencephalography
• CELF-4 Core Language Index
• WISC-IV Wechsler Intelligence Scale for Children
• VCI Verbal Comprehension Index
• DTI consisted of whole-brain 2x2x2 mm 3 isotropic acquisitions in the axial plane with 30 directions and b-value of 1000 s/mm 2 at 3T (Siemens VerioTM, Siemens Medical Solutions, Er Weg, Germany) using a modified monopolar Stejskal-Tanner sequence with TE of 70 ms, TR of 1 I s, spin-echo echoplanar sequence, a 32-channel head coil, maximal gradient strength of 45 mT/m, and a parallel acquisition factor of 2 with generalized autocalibrating partially parallel acquisition.
• Post-processing involved calculation of tensor eigenvalues, FA, and fiber tracking.
• DTI analyses examined left and right acoustic radiations, the thalamocortical projections connecting the medial geniculate nucleus to the primary auditory cortex of the superior temporal lobe.
• Regions of interest ROIs
• Fiber tracking by placing seeds within the left and right ROIs also allowed reconstruction of the fiber tracts of the left and right acoustic radiations and was used to confirm ROI placement.
• mean diffusivity MD
• axial diffusivity AD
• RD radial diffusivity
• M50 peak being the first peak with appropriate sensor-level topography immediately preceding Ml 00 and in a scoring window of 30-130 ms post-stimulus on set.
• M50 latency responses were scored using in-house MATLAB software correcting for baseline. The extended latency range of the M50 scoring window accommodated the longer M50 latencies observed in young children and ASD (Roberts et al. (2010) Autism Res. 3:8-18).
• M50 latency values across hemispheres revealed a statistically significant (p ⁇ 0.05) delay in M50 latency in ASD compared to that in TD. There were no between group differences in marginal mean FA, for either hemisphere, or for values collapsed across hemispheres.
• the group difference between slopes was not significant for either hemisphere (p>0.36). Collapsed across hemispheres there was a significant age-dependent shortening of M50 latency in both groups, that did not differ significantly in slope, although a significant difference in intercept reveals persistent M50 latency delay in ASD compared to that in TD.
• WM diffusion anisotropy and electrophysiological auditory cortex responses mature across development, with greater fractional anisotropy and earlier auditory latencies in older individuals. Individuals with ASD showed aberrant WM

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