Amber M. Leaver

Cortical Representation of Natural Complex Sounds: Effects of Acoustic Features and Auditory Object Category

How the brain processes complex sounds, like voices or musical instrument sounds, is currently not well understood. The features comprising the acoustic profiles of such sounds are thought to be represented by neurons responding to increasing degrees of complexity throughout auditory cortex, with complete auditory “objects” encoded by neurons (or small networks of neurons) in anterior superior temporal regions. Although specialized voice and speech–sound regions have been proposed, it is unclear how other types of complex natural sounds are processed within this object-processing pathway. Using functional magnetic resonance imaging, we sought to demonstrate spatially distinct patterns of category-selective activity in human auditory cortex, independent of semantic content and low-level acoustic features. Category-selective responses were identified in anterior superior temporal regions, consisting of clusters selective for musical instrument sounds and for human speech. An additional subregion was identified that was particularly selective for the acoustic–phonetic content of speech. In contrast, regions along the superior temporal plane closer to primary auditory cortex were not selective for stimulus category, responding instead to specific acoustic features embedded in natural sounds, such as spectral structure and temporal modulation. Our results support a hierarchical organization of the anteroventral auditory-processing stream, with the most anterior regions representing the complete acoustic signature of auditory objects.

Brain Activation during Anticipation of Sound Sequences

Music consists of sound sequences that require integration over time. As we become familiar with music, associations between notes, melodies, and entire symphonic movements become stronger and more complex. These associations can become so tight that, for example, hearing the end of one album track can elicit a robust image of the upcoming track while anticipating it in total silence. Here, we study this predictive “anticipatory imagery” at various stages throughout learning and investigate activity changes in corresponding neural structures using functional magnetic resonance imaging. Anticipatory imagery (in silence) for highly familiar naturalistic music was accompanied by pronounced activity in rostral prefrontal cortex (PFC) and premotor areas. Examining changes in the neural bases of anticipatory imagery during two stages of learning conditional associations between simple melodies, however, demonstrates the importance of fronto-striatal connections, consistent with a role of the basal ganglia in “training” frontal cortex (Pasupathy and Miller, 2005). Another striking change in neural resources during learning was a shift between caudal PFC earlier to rostral PFC later in learning. Our findings regarding musical anticipation and sound sequence learning are highly compatible with studies of motor sequence learning, suggesting common predictive mechanisms in both domains.

Structural Plasticity of the Hippocampus and Amygdala Induced by Electroconvulsive Therapy in Major Depression

BACKGROUND Electroconvulsive therapy (ECT) elicits a rapid and robust clinical response in patients with refractory depression. Neuroimaging measurements of structural plasticity relating to and predictive of ECT response may point to the mechanisms underlying rapid antidepressant effects and establish biomarkers to inform other treatments. Here, we determine the effects of diagnosis and of ECT on global and local variations of hippocampal and amygdala structures in major depression and predictors of ECT-related clinical response. METHODS Longitudinal changes in hippocampal and amygdala structures were examined in patients with major depression (N = 43, scanned three times: prior to ECT, after the second ECT session, and within 1 week of completing the ECT treatment series), referred for ECT as part of their standard clinical care. Cross-sectional comparisons with demographically similar controls (N = 32, scanned twice) established effects of diagnosis. RESULTS Patients showed smaller hippocampal volumes than controls at baseline (p < .04). Both the hippocampal and the amygdala volumes increased with ECT (p < .001) and in relation to symptom improvement (p < .01). Hippocampal volume at baseline predicted subsequent clinical response (p < .05). Shape analysis revealed pronounced morphometric changes in the anterior hippocampus and basolateral and centromedial amygdala. All structural measurements remained stable across time in controls. CONCLUSIONS ECT-induced neuroplasticity in the hippocampus and amygdala relates to improved clinical response and is pronounced in regions with prominent connections to ventromedial prefrontal cortex and other limbic structures. Smaller hippocampal volumes at baseline predict a more robust clinical response. Neurotrophic processes including neurogenesis shown in preclinical studies may underlie these structural changes.

Cortico-limbic morphology separates tinnitus from tinnitus distress

Tinnitus is a common auditory disorder characterized by a chronic ringing or buzzing “in the ear.”Despite the auditory-perceptual nature of this disorder, a growing number of studies have reported neuroanatomical differences in tinnitus patients outside the auditory-perceptual system. Some have used this evidence to characterize chronic tinnitus as dysregulation of the auditory system, either resulting from inefficient inhibitory control or through the formation of aversive associations with tinnitus. It remains unclear, however, whether these “non-auditory” anatomical markers of tinnitus are related to the tinnitus signal itself, or merely to negative emotional reactions to tinnitus (i.e., tinnitus distress). In the current study, we used anatomical MRI to identify neural markers of tinnitus, and measured their relationship to a variety of tinnitus characteristics and other factors often linked to tinnitus, such as hearing loss, depression, anxiety, and noise sensitivity. In a new cohort of participants, we confirmed that people with chronic tinnitus exhibit reduced gray matter in ventromedial prefrontal cortex (vmPFC) compared to controls matched for age and hearing loss. This effect was driven by reduced cortical surface area, and was not related to tinnitus distress, symptoms of depression or anxiety, noise sensitivity, or other factors. Instead, tinnitus distress was positively correlated with cortical thickness in the anterior insula in tinnitus patients, while symptoms of anxiety and depression were negatively correlated with cortical thickness in subcallosal anterior cingulate cortex (scACC) across all groups. Tinnitus patients also exhibited increased gyrification of dorsomedial prefrontal cortex (dmPFC), which was more severe in those patients with constant (vs. intermittent) tinnitus awareness. Our data suggest that the neural systems associated with chronic tinnitus are different from those involved in aversive or distressed reactions to tinnitus.

Segregation of Vowels and Consonants in Human Auditory Cortex: Evidence for Distributed Hierarchical Organization

The speech signal consists of a continuous stream of consonants and vowels, which must be de- and encoded in human auditory cortex to ensure the robust recognition and categorization of speech sounds. We used small-voxel functional magnetic resonance imaging to study information encoded in local brain activation patterns elicited by consonant-vowel syllables, and by a control set of noise bursts. First, activation of anterior–lateral superior temporal cortex was seen when controlling for unspecific acoustic processing (syllables versus band-passed noises, in a “classic” subtraction-based design). Second, a classifier algorithm, which was trained and tested iteratively on data from all subjects to discriminate local brain activation patterns, yielded separations of cortical patches discriminative of vowel category versus patches discriminative of stop-consonant category across the entire superior temporal cortex, yet with regional differences in average classification accuracy. Overlap (voxels correctly classifying both speech sound categories) was surprisingly sparse. Third, lending further plausibility to the results, classification of speech–noise differences was generally superior to speech–speech classifications, with the no\ exception of a left anterior region, where speech–speech classification accuracies were significantly better. These data demonstrate that acoustic–phonetic features are encoded in complex yet sparsely overlapping local patterns of neural activity distributed hierarchically across different regions of the auditory cortex. The redundancy apparent in these multiple patterns may partly explain the robustness of phonemic representations.

Functional MRI evidence for a role of ventral prefrontal cortex in tinnitus

It has long been known that subjective tinnitus, a constant or intermittent phantom sound perceived by 10 to 15% of the adult population, is not a purely auditory phenomenon but is also tied to limbic-related brain regions. Supporting evidence comes from data indicating that stress and emotion can modulate tinnitus, and from brain imaging studies showing functional and anatomical differences in limbic-related brain regions of tinnitus patients and controls. Recent studies from our lab revealed altered blood oxygen level-dependent (BOLD) responses to stimulation at the tinnitus frequency in the ventral striatum (specifically, the nucleus accumbens) and gray-matter reductions (i.e., anatomical changes) in ventromedial prefrontal cortex (vmPFC), of tinnitus patients compared to controls. The present study extended these findings by demonstrating functional differences in vmPFC between 20 tinnitus patients and 20 age-matched controls. Importantly, the observed BOLD response in vmPFC was positively correlated with tinnitus characteristics such as subjective loudness and the percent of time during which the tinnitus was perceived, whereas correlations with tinnitus handicap inventory scores and other variables known to be affected in tinnitus (e.g., depression, anxiety, noise sensitivity, hearing loss) were weaker or absent. This suggests that the observed group differences are indeed related to the strength of the tinnitus percept and not to an affective reaction to tinnitus. The results further corroborate vmPFC as a region of high interest for tinnitus research.This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Electroconvulsive therapy mediates neuroplasticity of white matter microstructure in major depression

Whether plasticity of white matter (WM) microstructure relates to therapeutic response in major depressive disorder (MDD) remains uncertain. We examined diffusion tensor imaging (DTI) correlates of WM structural connectivity in patients receiving electroconvulsive therapy (ECT), a rapidly acting treatment for severe MDD. Tract-Based Spatial Statistics (TBSS) applied to DTI data (61 directions, 2.5 mm3 voxel size) targeted voxel-level changes in fractional anisotropy (FA), and radial (RD), axial (AD) and mean diffusivity (MD) in major WM pathways in MDD patients (n=20, mean age: 41.15 years, 10.32 s.d.) scanned before ECT, after their second ECT and at transition to maintenance therapy. Comparisons made at baseline with demographically similar controls (n=28, mean age: 39.42 years, 12.20 s.d.) established effects of diagnosis. Controls were imaged twice to estimate scanning-related variance. Patients showed significant increases of FA in dorsal fronto-limbic circuits encompassing the anterior cingulum, forceps minor and left superior longitudinal fasciculus between baseline and transition to maintenance therapy (P<0.05, corrected). Decreases in RD and MD were observed in overlapping regions and the anterior thalamic radiation (P<0.05, corrected). Changes in DTI metrics associated with therapeutic response in tracts showing significant ECT effects differed between patients and controls. All measures remained stable across time in controls. Altered WM microstructure in pathways connecting frontal and limbic areas occur in MDD, are modulated by ECT and relate to therapeutic response. Increased FA together with decreased MD and RD, which trend towards normative values with treatment, suggest increased fiber integrity in dorsal fronto-limbic pathways involved in mood regulation.

Connectome and schizophrenia

Purpose of review The neural connections, interconnections and organized networks of the central nervous system (CNS), which represent the human connectome, are critical for intact brain function. Consequently, disturbances at any level or juncture of these networks may alter behaviour and/or lead to brain dysfunction. In this review, we focus on highlighting recent work using advanced imaging methods to address alterations in the structural and functional connectome in patients with schizophrenia. Recent findings Using structural, diffusion, resting-state and task-related functional imaging and advanced computational analysis methods such as graph theory, more than 200 publications have addressed different aspects of structural and/or functional connectivity in schizophrenia over the last year. These studies have focused on determining how brain networks differ from those in controls, interact with symptom profiles within and across diagnoses, interface with disease-related cognitive impairments and confer genetic risk for the disorder. Summary Much existing evidence supports the view that schizophrenia is a disorder of altered brain connectivity. Recent and continued characterization of the structural and functional connectome in schizophrenia patients have advanced our understanding of the neurobiology underlying clinical symptoms and cognitive impairments in a particular patient, their overlaps with other neuropsychiatric disorders sharing common features as well as the contributions of genetic risk factors. Although the clinical utility of the schizophrenia connectome remains to be realized, recent findings provide further promise that research in this area may lead to improved diagnosis, treatments and clinical outcomes.

Distinct cortical locations for integration of audiovisual speech and the McGurk effect.

Audiovisual (AV) speech integration is often studied using the McGurk effect, where the combination of specific incongruent auditory and visual speech cues produces the perception of a third illusory speech percept. Recently, several studies have implicated the posterior superior temporal sulcus (pSTS) in the McGurk effect; however, the exact roles of the pSTS and other brain areas in “correcting” differing AV sensory inputs remain unclear. Using functional magnetic resonance imaging (fMRI) in ten participants, we aimed to isolate brain areas specifically involved in processing congruent AV speech and the McGurk effect. Speech stimuli were composed of sounds and/or videos of consonant–vowel tokens resulting in four stimulus classes: congruent AV speech (AVCong), incongruent AV speech resulting in the McGurk effect (AVMcGurk), acoustic-only speech (AO), and visual-only speech (VO). In group- and single-subject analyses, left pSTS exhibited significantly greater fMRI signal for congruent AV speech (i.e., AVCong trials) than for both AO and VO trials. Right superior temporal gyrus, medial prefrontal cortex, and cerebellum were also identified. For McGurk speech (i.e., AVMcGurk trials), two clusters in the left posterior superior temporal gyrus (pSTG), just posterior to Heschl’s gyrus or on its border, exhibited greater fMRI signal than both AO and VO trials. We propose that while some brain areas, such as left pSTS, may be more critical for the integration of AV speech, other areas, such as left pSTG, may generate the “corrected” or merged percept arising from conflicting auditory and visual cues (i.e., as in the McGurk effect). These findings are consistent with the concept that posterior superior temporal areas represent part of a “dorsal auditory stream,” which is involved in multisensory integration, sensorimotor control, and optimal state estimation (Rauschecker and Scott, 2009).

Functional Topography of Human Auditory Cortex

Functional and anatomical studies have clearly demonstrated that auditory cortex is populated by multiple subfields. However, functional characterization of those fields has been largely the domain of animal electrophysiology, limiting the extent to which human and animal research can inform each other. In this study, we used high-resolution functional magnetic resonance imaging to characterize human auditory cortical subfields using a variety of low-level acoustic features in the spectral and temporal domains. Specifically, we show that topographic gradients of frequency preference, or tonotopy, extend along two axes in human auditory cortex, thus reconciling historical accounts of a tonotopic axis oriented medial to lateral along Heschls gyrus and more recent findings emphasizing tonotopic organization along the anterior–posterior axis. Contradictory findings regarding topographic organization according to temporal modulation rate in acoustic stimuli, or “periodotopy,” are also addressed. Although isolated subregions show a preference for high rates of amplitude-modulated white noise (AMWN) in our data, large-scale “periodotopic” organization was not found. Organization by AM rate was correlated with dominant pitch percepts in AMWN in many regions. In short, our data expose early auditory cortex chiefly as a frequency analyzer, and spectral frequency, as imposed by the sensory receptor surface in the cochlea, seems to be the dominant feature governing large-scale topographic organization across human auditory cortex. SIGNIFICANCE STATEMENT In this study, we examine the nature of topographic organization in human auditory cortex with fMRI. Topographic organization by spectral frequency (tonotopy) extended in two directions: medial to lateral, consistent with early neuroimaging studies, and anterior to posterior, consistent with more recent reports. Large-scale organization by rates of temporal modulation (periodotopy) was correlated with confounding spectral content of amplitude-modulated white-noise stimuli. Together, our results suggest that the organization of human auditory cortex is driven primarily by its response to spectral acoustic features, and large-scale periodotopy spanning across multiple regions is not supported. This fundamental information regarding the functional organization of early auditory cortex will inform our growing understanding of speech perception and the processing of other complex sounds.