Timothy P.L. Roberts

Auditory Cortex Accesses Phonological Categories: An MEG Mismatch Study

The studies presented here use an adapted oddball paradigm to show evidence that representations of discrete phonological categories are available to the human auditory cortex. Brain activity was recorded using a 37-channel biomagnetometer while eight subjects listened passively to synthetic speech sounds. In the phonological condition, which contrasted stimuli from an acoustic /d/-/t/ continuum, a magnetic mismatch field (MMF) was elicited in a sequence of stimuli in which phonological categories occurred in a many-to-one ratio, but no acoustic many-to-one ratio was present. In order to isolate the contribution of phonological categories to the MMF responses, the acoustic parameter of voice onset time, which distinguished standard and deviant stimuli, was also varied within the standard and deviant categories. No MMF was elicited in the acoustic condition, in which the acoustic distribution of stimuli was identical to the first experiment, but the many-to-one distribution of phonological categories was removed. The design of these studies makes it possible to demonstrate the all-or-nothing property of phonological category membership. This approach contrasts with a number of previous studies of phonetic perception using the mismatch paradigm, which have demonstrated the graded property of enhanced acoustic discrimination at or near phonetic category boundaries.

Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study.

Objective: To investigate, using functional MRI (fMRI), the neural network that is activated by the pain component of capsaicin-induced secondary mechanical hyperalgesia. Background: Mechanical hyperalgesia (i.e., pain to innocuous tactile stimuli) is a distressing symptom of neuropathic pain syndromes. Animal experiments suggest that alterations in central pain processing occur that render tactile stimuli capable of activating central pain-signaling neurons. A similar central sensitization can be produced experimentally with capsaicin. Methods: In nine healthy individuals the cerebral activation pattern resulting from cutaneous nonpainful mechanical stimulation at the dominant forearm was imaged using fMRI. Capsaicin was injected adjacent to the stimulation site to induce secondary mechanical hyperalgesia. The identical mechanical stimulation was then perceived as painful without changing the stimulus intensity and location. Both activation patterns were compared to isolate the specific pain-related component of mechanical hyperalgesia from the tactile component. Results: The pattern during nonpainful mechanical stimulation included contralateral primary sensory cortex (SI) and bilateral secondary sensory cortex (SII) activity. During hyperalgesia, significantly higher activation was found in the contralateral prefrontal cortex: the middle (Brodmann areas [BAs] 6, 8, and 9) and inferior frontal gyrus (BAs 44 and 45). No change was present within SI, SII, and the anterior cingulate cortex. Conclusions: Prefrontal activation is interpreted as a consequence of attention, cognitive evaluation, and planning of motor behavior in response to pain. The lack of activation of the anterior cingulate contrasts with physiologic pain after C-nociceptor stimulation. It might indicate differences in the processing of hyperalgesia and C-nociceptor pain or it might be due to habituation of affective sensations during hyperalgesia compared with acute capsaicin pain.

Validating γ Oscillations and Delayed Auditory Responses as Translational Biomarkers of Autism

BACKGROUND Difficulty modeling complex behavioral phenotypes in rodents (e.g., language) has hindered pathophysiological investigation and treatment development for autism spectrum disorders. Recent human neuroimaging studies, however, have identified functional biomarkers that can be more directly related to the abnormal neural dynamics of autism spectrum disorders. This study assessed the translational potential of auditory evoked-response endophenotypes of autism in parallel mouse and human studies of autism. METHODS Whole-cortex magnetoencephalography was recorded in 17 typically developing and 25 autistic children during auditory pure-tone presentation. Superior temporal gyrus activity was analyzed in time and frequency domains. Auditory evoked potentials were recorded in mice prenatally exposed to valproic acid (VPA) and analyzed with analogous methods. RESULTS The VPA-exposed mice demonstrated selective behavioral alterations related to autism, including reduced social interactions and ultrasonic vocalizations, increased repetitive self-grooming, and prepulse inhibition deficits. Autistic subjects and VPA-exposed mice showed a similar 10% latency delay in the N1/M100 evoked response and a reduction in γ frequency (30-50 Hz) phase-locking factor. Electrophysiological measures were associated with mouse behavioral deficits. In mice, γ phase-locking factor was correlated with expression of the autism risk gene neuroligin-3 and neural deficits were modulated by the mGluR5-receptor antagonist MPEP. CONCLUSIONS Results demonstrate a novel preclinical approach toward mechanistic understanding and treatment development for autism.

MEG detection of delayed auditory evoked responses in autism spectrum disorders: towards an imaging biomarker for autism

Motivated by auditory and speech deficits in autism spectrum disorders (ASD), the frequency dependence of superior temporal gyrus (STG) 50 msec (M50) and 100 msec (M100) neuromagnetic auditory evoked field responses in children with ASD and typically developing controls were evaluated. Whole‐cortex magnetoencephalography (MEG) was obtained from 17 typically developing children and 25 children with ASD. Subjects were presented tones with frequencies of 200, 300, 500, and 1,000 Hz, and left and right STG M50 and M100 STG activity was examined. No M50 latency or amplitude Group differences were observed. In the right hemisphere, a Group×Frequency ANOVA on M100 latency produced a main effect for Group (P=0.01), with an average M100 latency delay of 11 msec in children with ASD. In addition, only in the control group was the expected association of earlier M100 latencies in older than younger children observed. Group latency differences remained significant when hierarchical regression analyses partialed out M100 variance associated with age, IQ, and language ability (all P‐values <0.05). Examining the right‐hemisphere 500 Hz condition (where the largest latency differences were observed), a sensitivity of 75%, a specificity of 81%, and a positive predictive value (PPV) of 86% was obtained at a threshold of 116 msec. The M100 latency delay indicates disruption of encoding simple sensory information. Given similar findings in language impaired and nonlanguage impaired ASD subjects, a right‐hemisphere M100 latency delay appears to be an electrophysiological endophenotype for autism.

Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme

To evaluate the effects of a neutralizing anti‐vascular endothelial growth factor (anti‐VEGF) antibody on tumor microvascular permeability, a proposed indicator of angiogenesis, and tumor growth in a rodent malignant glioma model.

MRI using hyperpolarized noble gases

Abstract. The aim of this study was to review the physical basis of MRI using hyperpolarized noble gases as well as the present status of preclinical and clinical applications. Non-radioactive noble gases with a nuclear spin 1/2 (He-3, Xe-129) can be hyperpolarized by optical pumping. Polarization is transferred from circularly polarized laser light to the noble-gas atoms via alkali-metal vapors (spin exchange) or metastable atoms (metastability exchange). Hyperpolarization results in a non-equilibrium polarization five orders of magnitude higher than the Boltzmann equilibrium compensating for the several 1000 times lower density of noble gases as compared with liquid state hydrogen concentrations in tissue and allows for short imaging times. Hyperpolarization can be stored sufficiently long (3 h to 6 days) to allow for transport and application. Magnetic resonance systems require a broadband radio-frequency system – which is generally available for MR spectroscopy – and dedicated coils. The hyperpolarized gases are administered as inhalative “contrast agents” allowing for imaging of the airways and airspaces. Besides the known anesthetic effect of xenon, no adverse effects are observed in volunteers or patients. Pulse sequences are optimized to effectively use the non-renewable hyperpolarization before it decays or is destroyed, using fast low-flip-angles strategies to allow for dynamic/breath-hold imaging of highly diffusible (He) or soluble (Xe) gases with in vivo T1-times well below 1 min. Since helium is not absorbed in considerable amounts, its application is restricted to the lung. Xe-129 is also under investigation for imaging of white matter disease and functional studies of cerebral perfusion. Magnetic resonance imaging using hyperpolarized gases is emerging as a technical challenge and opportunity for the MR community. Preliminary experience suggests potential for functional imaging of pulmonary ventilation and cerebral perfusion.

Relating MEG Measured Motor Cortical Oscillations to resting γ-Aminobutyric acid (GABA) Concentration

The human motor cortex exhibits characteristic beta (15-30 Hz) and gamma oscillations (60-90 Hz), typically observed in the context of transient finger movement tasks. The functional significance of these oscillations, such as post-movement beta rebound (PMBR) and movement-related gamma synchrony (MRGS) remains unclear. Considerable animal and human non-invasive studies, however, suggest that the networks supporting these motor cortex oscillations depend critically on the inhibitory neurotransmitter γ-Aminobutyric acid (GABA). Despite such speculation, a direct relation between MEG measured motor cortex oscillatory power and frequency with resting GABA concentrations has not been demonstrated. In the present study, motor cortical responses were measured from 9 healthy adults while they performed a cued button-press task using their right index finger. In each participant, PMBR and MRGS measures were obtained from time-frequency plots obtained from primary motor (MI) sources, localized using beamformer differential source localization. For each participant, complimentary magnetic resonance spectroscopy (MRS) GABA measures aligned to the motor hand knob of the left central sulcus were also obtained. GABA concentration was estimated as the ratio of the motor cortex GABA integral to a cortical reference NAA resonance at 2 ppm. A significant linear relation was observed between MI GABA concentration and MRGS frequency (R(2)=0.46, p<0.05), with no association observed between GABA concentration and MRGS power. Conversely, a significant linear relation was observed between MI GABA concentration and PMBR power (R(2)=0.34, p<0.05), with no relation observed for GABA concentration and PMBR frequency. Finally, a significant negative linear relation between the participants age and MI gamma frequency was observed, such that older participants had a lower gamma frequency (R(2)=0.40, p<0.05). Present findings support a role for GABA in the generation and modulation of endogenous motor cortex rhythmic beta and gamma activity.

Latency of auditory evoked M100 as a function of tone frequency

THIS study investigated post-stimulus latency of the M100 component of auditory evoked fields as a function of tone frequency. A 37-channel biomagnetometer was used to record neuromagnetic fields over the temporal lobe in response to monaurally presented tones. M100 peaks in evoked field amplitude were found for each subject. The post-stimulus latency was observed to vary parabolically with tone frequency. Latencies as short as 99ms were found in response to mid-audio range frequencies (1000–2000 Hz), whereas lower (100–500 Hz) and higher (3000–5000 Hz) frequencies were associated with longer latencies (up to 153 ms). All fields gave M100 dipole localizations in auditory cortex. Although it was not possible to resolve spatial tonotopy, it appears that frequency information is encoded in the temporal evoked response.

Functional activity within brain tumors: a magnetic source imaging study.

OBJECTIVE To determine whether low-grade gliomas contain functional cortical activity more often than high-grade gliomas within radiologically defined abnormal tissue. METHODS Patients with intra-axial cerebral lesions located in the vicinity of eloquent brain cortex preoperatively underwent magnetic source imaging. A dual 37-channel biomagnetometer was used to perform the imaging. Evoked magnetic fields were analyzed using the single-equivalent dipole representation to ascertain the neuronal source. Stimuli included painless tactile somatosensory stimulation of fingers, toes, and lips and auditory presentation of pure sinusoidal tones. RESULTS A retrospective analysis of 106 nonconsecutively treated patients, who had undergone preoperative magnetic source imaging between February 1996 and December 1999, revealed that 24.5% of the patients had been at risk for neurological deficits, because functionally active tissue was located within or at the border of the tumor. Functional activity was found within the radiologically defined lesion in 18% of Grade 2 tumors, in 17% of Grade 3 tumors, and in 8% of Grade 4 tumors. CONCLUSION The results confirm that, regardless of tumor grade, intra-axial brain tumors may involve or directly border on functional cortex. The degree of involvement of functionally viable cortex appeared greater for low-grade tumors than for high-grade lesions. On the other hand, high-grade lesions were more likely to be associated with functional cortex at their margins or within peritumoral edema. To safely maximize tumor resection, preoperative functional imaging and intraoperative electrophysiological mapping of the cerebral cortex and the white matter tracts are deemed necessary.

Tumor microvascular changes in antiangiogenic treatment: Assessment by magnetic resonance contrast media of different molecular weights

To test magnetic resonance (MR) contrast media of different molecular weights (MWs) for their potential to characterize noninvasively microvascular changes in an experimental tumor treatment model.