Ashesh D. Mehta

Clinical applications of the functional connectome.

Central to the development of clinical applications of functional connectomics for neurology and psychiatry is the discovery and validation of biomarkers. Resting state fMRI (R-fMRI) is emerging as a mainstream approach for imaging-based biomarker identification, detecting variations in the functional connectome that can be attributed to clinical variables (e.g., diagnostic status). Despite growing enthusiasm, many challenges remain. Here, we assess evidence of the readiness of R-fMRI based functional connectomics to lead to clinically meaningful biomarker identification through the lens of the criteria used to evaluate clinical tests (i.e., validity, reliability, sensitivity, specificity, and applicability). We focus on current R-fMRI-based prediction efforts, and survey R-fMRI used for neurosurgical planning. We identify gaps and needs for R-fMRI-based biomarker identification, highlighting the potential of emerging conceptual, analytical and cultural innovations (e.g., the Research Domain Criteria Project (RDoC), open science initiatives, and Big Data) to address them. Additionally, we note the need to expand future efforts beyond identification of biomarkers for disease status alone to include clinical variables related to risk, expected treatment response and prognosis.

Neurophysiological investigation of spontaneous correlated and anticorrelated fluctuations of the BOLD signal.

Analyses of intrinsic fMRI BOLD signal fluctuations reliably reveal correlated and anticorrelated functional networks in the brain. Because the BOLD signal is an indirect measure of neuronal activity and anticorrelations can be introduced by preprocessing steps, such as global signal regression, the neurophysiological significance of correlated and anticorrelated BOLD fluctuations is a source of debate. Here, we address this question by examining the correspondence between the spatial organization of correlated BOLD fluctuations and correlated fluctuations in electrophysiological high γ power signals recorded directly from the cortical surface of 5 patients. We demonstrate that both positive and negative BOLD correlations have neurophysiological correlates reflected in fluctuations of spontaneous neuronal activity. Although applying global signal regression to BOLD signals results in some BOLD anticorrelations that are not apparent in the ECoG data, it enhances the neuronal-hemodynamic correspondence overall. Together, these findings provide support for the neurophysiological fidelity of BOLD correlations and anticorrelations.

Tuning of the Human Neocortex to the Temporal Dynamics of Attended Events

Previous studies raise the hypothesis that attentional bias in the phase of neocortical excitability fluctuations (oscillations) represents a fundamental mechanism for tuning the brain to the temporal dynamics of task-relevant event patterns. To evaluate this hypothesis, we recorded intracranial electrocortical activity in human epilepsy patients while they performed an audiovisual stream selection task. Consistent with our hypothesis, (1) attentional modulation of oscillatory entrainment operates in a distinct network of areas including auditory, visual, posterior parietal, inferior motor, inferior frontal and superior midline frontal cortex, (2) the degree of oscillatory entrainment depends on the predictability of the stimulus stream, and (3) the attentional phase shift of entrained oscillation cooccurs with classical attentional effects observed on phase-locked evoked activity in sensory-specific areas but seems to operate on entrained low-frequency oscillations that cannot be explained by sensory activity evoked at the rate of stimulation. Thus, attentional entrainment appears to tune a network of brain areas to the temporal dynamics of behaviorally relevant event streams, contributing to its perceptual and behavioral selection.

A human intracranial study of long-range oscillatory coherence across a frontal-occipital-hippocampal brain network during visual object processing.

Visual object-recognition is thought to involve activation of a distributed network of cortical regions, nodes of which include the lateral prefrontal cortex, the so-called lateral occipital complex (LOC), and the hippocampal formation. It has been proposed that long-range oscillatory synchronization is a major mode of coordinating such a distributed network. Here, intracranial recordings were made from three humans as they performed a challenging visual object-recognition task that required them to identify barely recognizable fragmented line-drawings of common objects. Subdural electrodes were placed over the prefrontal cortex and LOC, and depth electrodes were placed within the hippocampal formation. Robust beta-band coherence was evident in all subjects during processing of recognizable fragmented images. Significantly lower coherence was evident during processing of unrecognizable scrambled versions of the same. The results indicate that transient beta-band oscillatory coupling between these three distributed cortical regions may reflect a mechanism for effective communication during visual object processing.

Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis

Significance Rheumatoid arthritis (RA) is a chronic, prevalent, and disabling autoimmune disease that occurs when inflammation damages joints. Recent advances in neuroscience and immunology have mapped neural circuits that regulate the onset and resolution of inflammation. In one circuit, termed “the inflammatory reflex,” action potentials transmitted in the vagus nerve inhibit the production of tumor necrosis factor (TNF), an inflammatory molecule that is a major therapeutic target in RA. Although studied in animal models of arthritis and other inflammatory diseases, whether electrical stimulation of the vagus nerve can inhibit TNF production in humans has remained unknown. The positive mechanistic results reported here extend the preclinical data to the clinic and reveal that vagus nerve stimulation inhibits TNF and attenuates disease severity in RA patients. Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.

Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex

Epileptic cortex is characterized by paroxysmal electrical discharges. Analysis of these interictal discharges typically manifests as spike-wave complexes on electroencephalography, and plays a critical role in diagnosing and treating epilepsy. Despite their fundamental importance, little is known about the neurophysiological mechanisms generating these events in human focal epilepsy. Using three different systems of microelectrodes, we recorded local field potentials and single-unit action potentials during interictal discharges in patients with medically intractable focal epilepsy undergoing diagnostic workup for localization of seizure foci. We studied 336 single units in 20 patients. Ten different cortical areas and the hippocampus, including regions both inside and outside the seizure focus, were sampled. In three of these patients, high density microelectrode arrays simultaneously recorded between 43 and 166 single units from a small (4 mm x 4 mm) patch of cortex. We examined how the firing rates of individual neurons changed during interictal discharges by determining whether the firing rate during the event was the same, above or below a median baseline firing rate estimated from interictal discharge-free periods (Kruskal-Wallis one-way analysis, P<0.05). Only 48% of the recorded units showed such a modulation in firing rate within 500 ms of the discharge. Units modulated during the discharge exhibited significantly higher baseline firing and bursting rates than unmodulated units. As expected, many units (27% of the modulated population) showed an increase in firing rate during the fast segment of the discharge (+ or - 35 ms from the peak of the discharge), while 50% showed a decrease during the slow wave. Notably, in direct contrast to predictions based on models of a pure paroxysmal depolarizing shift, 7.7% of modulated units recorded in or near the seizure focus showed a decrease in activity well ahead (0-300 ms) of the discharge onset, while 12.2% of units increased in activity in this period. No such pre-discharge changes were seen in regions well outside the seizure focus. In many recordings there was also a decrease in broadband field potential activity during this same pre-discharge period. The different patterns of interictal discharge-modulated firing were classified into more than 15 different categories. This heterogeneity in single unit activity was present within small cortical regions as well as inside and outside the seizure onset zone, suggesting that interictal epileptiform activity in patients with epilepsy is not a simple paroxysm of hypersynchronous excitatory activity, but rather represents an interplay of multiple distinct neuronal types within complex neuronal networks.

Intrinsic functional architecture predicts electrically evoked responses in the human brain

Adaptive brain function is characterized by dynamic interactions within and between neuronal circuits, often occurring at the time scale of milliseconds. These complex interactions between adjacent and noncontiguous brain areas depend on a functional architecture that is maintained even in the absence of input. Functional MRI studies carried out during rest (R-fMRI) suggest that this architecture is represented in low-frequency (<0.1 Hz) spontaneous fluctuations in the blood oxygen level-dependent signal that are correlated within spatially distributed networks of brain areas. These networks, collectively referred to as the brains intrinsic functional architecture, exhibit a remarkable correspondence with patterns of task-evoked coactivation as well as maps of anatomical connectivity. Despite this striking correspondence, there is no direct evidence that this intrinsic architecture forms the scaffold that gives rise to faster processes relevant to information processing and seizure spread. Here, we demonstrate that the spatial distribution and magnitude of temporally correlated low-frequency fluctuations observed with R-fMRI during rest predict the pattern and magnitude of corticocortical evoked potentials elicited within 500 ms after single-pulse electrical stimulation of the cerebral cortex with intracranial electrodes. Across individuals, this relationship was found to be independent of the specific regions and functional systems probed. Our findings bridge the immense divide between the temporal resolutions of these distinct measures of brain function and provide strong support for the idea that the low-frequency signal fluctuations observed with R-fMRI maintain and update the intrinsic architecture underlying the brains repertoire of functional responses.

Blood volume and hemoglobin oxygenation response following electrical stimulation of human cortex

Our understanding of perfusion-based human brain mapping techniques relies on a detailed knowledge of the relationship between neuronal activity and cerebrovascular hemodynamics. We performed optical imaging of intrinsic signals at wavelengths sensitive to total hemoglobin (Hbt; which correlate with cerebral blood volume (CBV)) and deoxygenated hemoglobin (Hbr) directly in humans during neurosurgical operations and investigated the optical signals associated with bipolar cortical stimulation at a range of amplitudes. Cortical stimulation elicited a rapid focal increase in Hbr (initial dip) in all subjects. An equally rapid increase in Hbt (<200 ms), with a slightly higher signal-to-noise ratio, was also highly localized for <2 s in spite of the non-columnar nature of the stimulus, after which the signal spread to adjacent gyri. A later decrease in Hbr (>3 s), which is relevant to the blood oxygen level dependent (BOLD) signal, was poorly localized. Increasing the stimulus amplitude elicited a linear increase in the area of the optical signal for Hbt and the initial dip but not the late decrease in Hbr, and a nonlinear increase in optical signal amplitude with a plateau effect for initial dip, Hbt and late decrease in Hbr.

Spatiotemporal structure of intracranial electric fields induced by transcranial electric stimulation in humans and nonhuman primates.

Transcranial electric stimulation (TES) is an emerging technique, developed to non-invasively modulate brain function. However, the spatiotemporal distribution of the intracranial electric fields induced by TES remains poorly understood. In particular, it is unclear how much current actually reaches the brain, and how it distributes across the brain. Lack of this basic information precludes a firm mechanistic understanding of TES effects. In this study we directly measure the spatial and temporal characteristics of the electric field generated by TES using stereotactic EEG (s-EEG) electrode arrays implanted in cebus monkeys and surgical epilepsy patients. We found a small frequency dependent decrease (10%) in magnitudes of TES induced potentials and negligible phase shifts over space. Electric field strengths were strongest in superficial brain regions with maximum values of about 0.5 mV/mm. Our results provide crucial information of the underlying biophysics in TES applications in humans and the optimization and design of TES stimulation protocols. In addition, our findings have broad implications concerning electric field propagation in non-invasive recording techniques such as EEG/MEG.

Temporal Dependence in Uncoupling of Blood Volume and Oxygenation during Interictal Epileptiform Events in Rat Neocortex

We investigated the dynamic spatiotemporal relationships of cerebral blood volume (CBV), deoxygenated hemoglobin (Hbr), and light scatter (LS) associated with interictal epileptiform events with multiwavelength optical recording of intrinsic signals and simultaneous field potential recording. Interictal spikes (IISs) were induced with iontophoresis of bicuculline methiodide in rat neocortex. Intrinsic signal changes appeared as early as 100 msec after the IIS at all wavelengths and could be appreciated after only a single IIS. Initially, the largest signal arose from a focal increase in deoxygenation, which lasted for ∼2 sec, consistent with an “initial dip.” An equally early focal increase in CBV had a smaller amplitude than the Hbr signal until >2 sec after the IIS, when its amplitude surpassed that of the Hbr signal but also spread to a larger, less focal area. The most spatially restricted and smallest amplitude signal was produced by LS. A later hyperoxygenation, or increase in blood oxygenation level-dependent signal, was often seen in the draining veins but inconsistently seen in the IIS focus. An inverted optical signal was recorded at all wavelengths from multiple regions in the surrounding cortex within 100 msec of the IIS. We therefore conclude that the IIS induces a rapid increase in metabolic demand, which cannot be met by a rapid, initially focal but small increase in CBV that results in a prolonged increase in Hbr (epileptic dip in oxygenated hemoglobin). The inverted optical signal in the surround arises from a decrease in CBV and a decrease in Hbr, likely resulting from a combination of shunting of CBV to the focus and decreased metabolic demand resulting from decreased neuronal activity, consistent with “surround inhibition.”