Fast neurotransmitter identity of MCH neurons: Do contents depend on context?

Hypothalamic melanin-concentrating hormone (MCH) neurons participate in many fundamental neuroendocrine processes. While some of their effects can be attributed to MCH itself, others appear to depend on co-released neurotransmitters. Historically, the subject of fast neurotransmitter co-release from MCH neurons has been contentious, with data to support MCH neurons releasing GABA, glutamate, both, and neither. Rather than assuming a position in that debate, this review considers the evidence for all sides and presents an alternative explanation: neurochemical identity, including classical neurotransmitter content, is subject to change. With an emphasis on the variability of experimental details, we posit that MCH neurons may release GABA and/or glutamate at different points according to environmental and contextual factors. Through the lens of the MCH system, we offer evidence that the field of neuroendocrinology would benefit from a more nuanced and dynamic interpretation of neurotransmitter identity.

Assessing the state of consciousness for individual patients using complex, statistical stimuli.

Patients with prolonged disorders of consciousness (PDOC) are often unable to communicate their state of consciousness. Determining the latter is essential for the patient's care and prospects of recovery. Auditory stimulation in combination with neural recordings is a promising technique towards an objective assessment of conscious awareness. Here, we investigated the potential of complex, acoustic stimuli to elicit EEG responses suitable for classifying multiple subject groups, from unconscious to responding. We presented naturalistic auditory textures with unexpectedly changing statistics to human listeners. Awake, active listeners were asked to indicate the change by button press, while all other groups (awake passive, asleep, minimally conscious state (MCS), and unresponsive wakefulness syndrome (UWS)) listened passively. We quantified the evoked potential at stimulus onset and change in stimulus statistics, as well as the complexity of neural response during the change of stimulus statistics. On the group level, onset and change potentials classified patients and healthy controls successfully but failed to differentiate between the UWS and MCS groups. Conversely, the Lempel-Ziv complexity of the scalp-level potential allowed reliable differentiation between UWS and MCS even for individual subjects, when compared with the clinical assessment aligned to the EEG measurements. The accuracy appears to improve further when taking the latest available clinical diagnosis into account. In summary, EEG signal complexity during onset and changes in complex acoustic stimuli provides an objective criterion for distinguishing states of consciousness in clinical patients. These results suggest EEG-recordings as a cost-effective tool to choose appropriate treatments for non-responsive PDOC patients.

Interaction among the components of multiple auditory steady-state responses: enhancement in tinnitus patients, inhibition in controls.

Amplitude and phase of steady-state signals recorded in response to amplitude-modulated (AM) sine tones vary over time, suggesting that the steady-state response (SSR) reflects not only stimulus input but also its interaction with other input streams or internally generated signals. Alterations of the interaction between simultaneous SSRs associated with tinnitus were studied by recording the magnetic field evoked by AM-tones with one of three carrier and one of three modulation frequencies. Single AM-tones were presented in single presentation mode and superpositions of three AM-tones differing in carrier and modulation frequency in multiple presentation mode. Modulation frequency-specific SSR components were recovered by bandpass filtering. Compared with single mode, in multiple mode SSR amplitude was reduced in healthy controls, but increased in tinnitus patients. Thus, while in controls multiple response components seem to reciprocally inhibit one another, in tinnitus reciprocal facilitation seems to predominate. Reciprocal inhibition was unrelated to the phase coherence among SSR components, but was correlated with the frequency of phase slips, indicating that the lateral interaction among SSR components acts in a quasi-paroxysmal manner and manifests itself in terms of a random train of phase reset events. Phase slips were more frequent in patients than controls both in single and multiple mode. Together, these findings indicate that lateral or surround inhibition of single units in auditory cortex is reduced and suggest that in-field inhibition is increased in tinnitus.

Additional neuromagnetic source activity outside the auditory cortex in duration discrimination correlates with behavioural ability.

In magneto- and electroencephalographic experiments on an oddball paradigm we compared the components of the auditory evoked fields and potentials of "attend" with "nonattend" conditions in 17 subjects. The former consisted of the performance of a duration discrimination task, where we observed augmented activity for the auditory sustained response. A multiple source analysis showed this effect mainly stemming from a third source outside the auditory cortices. The dipole moment of this specific activation was increased by 150% under the attend condition. Having anatomical 3D MRI data sets of 12 subjects the likely location of the third source was shown to be within the area of the precuneus or the posterior cingulate gyrus, which, along with its waveform, suggests it to be a CNV equivalent. Further, the dipole moment is correlated significantly to the subjects' psychometrically derived discriminative abilities.

Is frontal lobe involved in the generation of auditory evoked P50?

This study examined the functional substrate of P50 suppression. Auditory evoked potentials (AEPs) and magnetic fields (AEFs) were recorded from healthy subjects simultaneously and analyzed using spatio-temporal source analysis. The resulting equivalent dipole model for the AEP consisted of one source in the auditory cortex (AC) of each hemisphere and an radially oriented medial frontal source, both with maximum AEP activity around 50 ms. The frontal source was functionally separated from the AC sources since it peaked significantly later and showed significantly larger P50 amplitude suppression. P30m showed neither suppression nor substantial frontal activity. In sum, this study relates P50 suppression to reduction of AC source activity and is the first to yield direct evidence for frontal involvement in P50 suppression.

Fast temporal interactions in human auditory cortex.

The temporal resolution of the human primary auditory cortex (AC) was studied using middle-latency evoked fields. Paired sounds with either the same or different spectral characteristics were presented with gaps between the sounds of 1, 4, 8 and 14 ms. Spatio-temporal modelling showed (1) that the response to the second sound was recognizable with gaps of 1 ms and rapidly increased in amplitude with increasing gap durations, (2) an enhanced N40m amplitude at gaps > 4 ms, (3) delayed N19m-P30m latencies when the stimuli were different. The median psychoacoustical thresholds were 1.6 ms for the same stimuli and 2.5 ms for different stimuli, confirming the electrophysiological evidence for rapid pattern-specific temporal processing in human primary auditory cortex.

Deconvolution of 40 Hz steady-state fields reveals two overlapping source activities of the human auditory cortex.

Steady-state auditory evoked fields were recorded from 15 subjects using a whole head MEG system. Stimuli were 800 ms trains of binaural clicks with constant stimulus onset asynchrony (SOA). Seven different SOA settings (19, 21, 23, 25, 27, 29 and 31 ms) were used to give click rates near 40 Hz. Transient responses to each click were reconstructed using a new algorithm that deconvoluted the averaged responses to the different trains. Spatio-temporal multiple dipole modelling in relation to 3D MRI scans revealed two overlapping source components in both the left and right auditory cortex. The primary sources in the medial part of Heschl's gyrus exhibited a N19-P30-N40 m pattern. The secondary, weaker sources at more lateral sites on Heschl's gyrus showed a N24-P36-N46 m pattern. When applied to transient middle latency auditory evoked fields (MAEFs) recorded at SOAs of 95-135 ms, the primary sources imaged activities similar to the deconvoluted steady-state responses, but the secondary source activities were inconsistent. Linear summation of the deconvoluted source waveforms accounted for more than 96% of the steady-state variance. This indicates that the primary activity of the auditory cortex remains constant up to high stimulation rates and is not specifically enhanced around 40 Hz.

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria.

Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased. This hypothesis was tested by measuring brain Phe in patients with PKU by quantitative 1H magnetic resonance spectroscopy during an oral Phe challenge with and without additional supplementation with all other LNAAs. Baseline plasma Phe was approximately 1,000 micromol/l and brain Phe was approximately 250 micromol/l in both series. Without LNAA supplementation, brain Phe increased to approximately 400 micromol/l after the oral Phe load. Electroencephalogram (EEG) spectral analysis revealed acutely disturbed brain activity. With concurrent LNAA supplementation, Phe influx was completely blocked and there was no slowing of EEG activity. These results are relevant for further characterization of the LNAA carrier and of the pathophysiology underlying brain dysfunction in PKU and for treatment of patients with PKU, as brain function might be improved by continued LNAA supplementation.