Increased Neural Activity in Mesostriatal Regions after Prefrontal Transcranial Direct Current Stimulation and l-DOPA Administration.

Dopamine dysfunction is associated with a wide range of neuropsychiatric disorders commonly treated pharmacologically or invasively. Recent studies provide evidence for a nonpharmacological and noninvasive alternative that allows similar manipulation of the dopaminergic system: transcranial direct current stimulation (tDCS). In rodents, tDCS has been shown to increase neural activity in subcortical parts of the dopaminergic system, and recent studies in humans provide evidence that tDCS over prefrontal regions induces striatal dopamine release and affects reward-related behavior. Based on these findings, we used fMRI in healthy human participants and measured the fractional amplitude of low-frequency fluctuations to assess spontaneous neural activity strength in regions of the mesostriatal dopamine system before and after tDCS over prefrontal regions (n = 40, 22 females). In a second study, we examined the effect of a single dose of the dopamine precursor levodopa (l-DOPA) on mesostriatal fractional amplitude of low-frequency fluctuation values in male humans (n = 22) and compared the results between both studies. We found that prefrontal tDCS and l-DOPA both enhance neural activity in core regions of the dopaminergic system and show similar subcortical activation patterns. We furthermore assessed the spatial similarity of whole-brain statistical parametric maps, indicating tDCS- and l-DOPA-induced activation, and >100 neuronal receptor gene expression maps based on transcriptional data from the Allen Institute for Brain Science. In line with a specific activation of the dopaminergic system, we found that both interventions predominantly activated regions with high expression levels of the dopamine receptors D2 and D3.SIGNIFICANCE STATEMENT Studies in animals and humans provide evidence that transcranial direct current stimulation (tDCS) allows a manipulation of the dopaminergic system. Based on these findings, we used fMRI to assess changes in spontaneous neural activity strength in the human dopaminergic system after prefrontal tDCS compared with the administration of the dopamine precursor and standard anti-Parkinson drug levodopa (l-DOPA). We found that prefrontal tDCS and l-DOPA both enhance neural activity in core regions of the dopaminergic system and show similar subcortical activation patterns. Using whole-brain transcriptional data of >100 neuronal receptor genes, we found that both interventions specifically activated regions with high expression levels of the dopamine receptors D2 and D3.

Beyond correlation: functional OPTO-MAgnetic Integration Concept (OPTOMAIC) to reveal the brain-wide signature of local neuronal signals-of-interest.

Significance: Due to the vascular origin of the fMRI signal, the spatiotemporally precise interpretation of the blood oxygen level-dependent (BOLD) response as brain-wide correlate of neuronal activity is limited. Optical fiber-based neuronal calcium recordings provide a specific and temporally highly resolved signal yet lacking brain-wide coverage. The cross-modal integration of both modalities holds the potential for unique synergies. Aim: The OPTO-MAgnetic Integration Concept (OPTOMAIC) extracts the very fraction of the BOLD response that reacts to optically recorded neuronal signals-of-interest. Approach and Results: First, OPTOMAIC identifies the trials containing neuronal signal-of-interest (SoI) in the optical recordings. The long duration of the BOLD response is considered by calculating and thresholding neuronal interevent intervals. The resulting optical regression vector is probed for a positive BOLD response with single-event and single-voxel resolution, generating a BOLD response matrix containing only those events and voxels with both a neuronal SoI and a positive fMRI signal increase. Last, the onset of the BOLD response is being quantified, representing the section of the BOLD response most reliably reporting at least components of the neuronal signal. Conclusions: The seven OPTOMAIC steps result in a brain-wide BOLD signature reflecting the underlying neuronal SoI with utmost cross-modal integration depth and taking full advantage of the specific strengths of each method.

Brain states govern the spatio-temporal dynamics of resting-state functional connectivity.

Previously, using simultaneous resting-state functional magnetic resonance imaging (fMRI) and photometry-based neuronal calcium recordings in the anesthetized rat, we identified blood oxygenation level-dependent (BOLD) responses directly related to slow calcium waves, revealing a cortex-wide and spatially organized correlate of locally recorded neuronal activity (Schwalm et al., 2017). Here, using the same techniques, we investigate two distinct cortical activity states: persistent activity, in which compartmentalized network dynamics were observed; and slow wave activity, dominated by a cortex-wide BOLD component, suggesting a strong functional coupling of inter-cortical activity. During slow wave activity, we find a correlation between the occurring slow wave events and the strength of functional connectivity between different cortical areas. These findings suggest that down-up transitions of neuronal excitability can drive cortex-wide functional connectivity. This study provides further evidence that changes in functional connectivity are dependent on the brain's current state, directly linked to the generation of slow waves.

Antero-Posterior vs. Lateral Vestibular Input Processing in Human Visual Cortex.

Visuo-vestibular integration is crucial for locomotion, yet the cortical mechanisms involved remain poorly understood. We combined binaural monopolar galvanic vestibular stimulation (GVS) and functional magnetic resonance imaging (fMRI) to characterize the cortical networks activated during antero-posterior and lateral stimulations in humans. We focused on functional areas that selectively respond to egomotion-consistent optic flow patterns: the human middle temporal complex (hMT+), V6, the ventral intraparietal (VIP) area, the cingulate sulcus visual (CSv) area and the posterior insular cortex (PIC). Areas hMT+, CSv, and PIC were equivalently responsive during lateral and antero-posterior GVS while areas VIP and V6 were highly activated during antero-posterior GVS, but remained silent during lateral GVS. Using psychophysiological interaction (PPI) analyses, we confirmed that a cortical network including areas V6 and VIP is engaged during antero-posterior GVS. Our results suggest that V6 and VIP play a specific role in processing multisensory signals specific to locomotion during navigation.

Cortex-wide BOLD fMRI activity reflects locally-recorded slow oscillation-associated calcium waves.

Spontaneous slow oscillation-associated slow wave activity represents an internally generated state which is characterized by alternations of network quiescence and stereotypical episodes of neuronal activity - slow wave events. However, it remains unclear which macroscopic signal is related to these active periods of the slow wave rhythm. We used optic fiber-based calcium recordings of local neural populations in cortex and thalamus to detect neurophysiologically defined slow calcium waves in isoflurane anesthetized rats. The individual slow wave events were used for an event-related analysis of simultaneously acquired whole-brain BOLD fMRI. We identified BOLD responses directly related to onsets of slow calcium waves, revealing a cortex-wide BOLD correlate: the entire cortex was engaged in this specific type of slow wave activity. These findings demonstrate a direct relation of defined neurophysiological events to a specific BOLD activity pattern and were confirmed for ongoing slow wave activity by independent component and seed-based analyses.

The spatial range of peripheral collinear facilitation.

Contrast detection thresholds for a central Gabor patch (target) can be modulated by the presence of co-oriented and collinear high contrast Gabors flankers. In foveal vision collinear facilitation can be observed for target-to-flankers relative distances beyond two times the wavelength (λ) of the Gabor's carrier, while for shorter relative distances (<2λ) there is suppression. These modulatory influences seem to disappear after 12λ. In this study, we measured contrast detection thresholds for different spatial frequencies (1, 4 and 6 cpd) and target-to-flankers relative distances ranging from 6 to 16λ, but with collinear configurations presented in near periphery at 4° of eccentricity. Results showed that in near periphery collinear facilitation extends beyond 12λ for the higher spatial frequencies tested (4 and 6 cpd), while it decays already at 10λ for the lowest spatial frequency used (i.e., 1 cpd). In addition, we found that increasing the spatial frequency the peak of collinear facilitation shifts towards larger target-to-flankers relative distances (expressed as multiples of the stimulus wavelength), an effect never reported neither for near peripheral nor for central vision. The results suggest that the peak and the spatial extent of collinear facilitation in near periphery depend on the spatial frequency of the stimuli used.

Time compression increases with eccentricity: a magnocellular property.

Accurate time perception is crucial in peripheral vision especially for the spatial perception during actions. To investigate the dynamics of time perception in peripheral vision, parvocellular-biased and magnocellular-biased flashes were presented at different eccentricities (0-48 degrees ) in an interflash interval discrimination task. Results showed an increase in time compression with eccentricity for both stimuli (magnocellular-biased and parvocellular-biased flashes). Nevertheless, when stimulus visibility was 'equalized' across the visual field, the increase in time compression was only found for magnocellular-biased stimuli. Thus, we suggest that the magnocellular pathway accounts for time underestimation. Moreover, its increase with eccentricity could be an inherent property of the magnocellular system more than a result of a decrease in stimulus visibility.