Assessment of the excitation-inhibition ratio in the Fmr1 KO2 mouse using neuronal oscillation dynamics.

In vitro and ex vivo studies have shown consistent indications of hyperexcitability in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mouse model of autism spectrum disorder. We recently introduced a method to quantify network-level functional excitation-inhibition ratio from the neuronal oscillations. Here, we used this measure to study whether the implicated synaptic excitation-inhibition disturbances translate to disturbances in network physiology in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) gene knockout model. Vigilance-state scoring was used to extract segments of inactive wakefulness as an equivalent behavioral condition to the human resting-state and, subsequently, we performed high-frequency resolution analysis of the functional excitation-inhibition biomarker, long-range temporal correlations, and spectral power. We corroborated earlier studies showing increased high-frequency power in Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mice. Long-range temporal correlations were higher in the gamma frequency ranges. Contrary to expectations, functional excitation-inhibition was lower in the knockout mice in high frequency ranges, suggesting more inhibition-dominated networks. Exposure to the Gamma-aminobutyric acid (GABA)-agonist clonazepam decreased the functional excitation-inhibition in both genotypes, confirming that increasing inhibitory tone results in a reduction of functional excitation-inhibition. In addition, clonazepam decreased electroencephalogram power and increased long-range temporal correlations in both genotypes. These findings show applicability of these new resting-state electroencephalogram biomarkers to animal for translational studies and allow investigation of the effects of lower-level disturbances in excitation-inhibition balance.

Multimodal assessment of the GABA system in patients with fragile-X syndrome and neurofibromatosis of type 1.

Fragile-X syndrome (FXS) and Neurofibromatosis of type 1 (NF-1) are two monogenic disorders sharing neurobehavioral symptoms and pathophysiological mechanisms. Namely, preclinical models of both conditions show overactivity of the mTOR signaling pathway as well as GABAergic alterations. However, despite its potential clinical relevance for these disorders, the GABAergic system has not been systematically studied in humans. In the present study, we used an extensive transcranial magnetic stimulation (TMS) assessment battery in combination with magnetic resonance spectroscopy (MRS) to provide a comprehensive picture of the main inhibitory neurotransmitter system in patients with FXS and NF1. Forty-three participants took part in the TMS session (15 FXS, 10 NF1, 18 controls) and 36 in the MRS session (11 FXS, 14 NF1, 11 controls). Results show that, in comparison to healthy control participants, individuals with FXS and NF1 display lower GABA concentration levels as measured with MRS. TMS result show that FXS patients present increased GABAB-mediated inhibition compared to controls and NF1 patients, and that GABAA-mediated intracortical inhibition was associated with increased excitability specifically in the FXS groups. In line with previous reports, correlational analyses between MRS and TMS measures did not show significant relationships between GABA-related metrics, but several TMS measures correlated with glutamate+glutamine (Glx) levels assessed with MRS. Overall, these results suggest a partial overlap in neurophysiological alterations involving the GABA system in NF1 and FXS, and support the hypothesis that MRS and TMS assess different aspects of the neurotransmitter systems.

Assessment of cortical inhibition depends on inter individual differences in the excitatory neural populations activated by transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is used to probe inhibitory intracortical neurotransmission and has been used to infer the neurobiological dysfunction that may underly several neurological disorders. One technique, short-interval intracortical inhibition (SICI), indexes gamma-aminobutyric acid (GABA) mediated inhibitory activity and is a promising biomarker. However emerging evidence suggests SICI does not exclusively represent GABAergic activity because it may be influenced by inter-individual differences in the specific excitatory neural populations activated by TMS. Here we used the latency of TMS motor evoked potentials (MEPs) to index these inter-individual differences, and found that a significant proportion of the observed variability in SICI magnitude was accounted for by MEP latency, r = - 0.57, r2 = 0.33, p = .014. We conclude that SICI is influenced by inter-individual differences in the excitatory neural populations activated by TMS, reducing the precision of this GABAergic probe. Interpreting SICI measures in the context of MEP latency may facilitate a more precise assessment of GABAergic intracortical inhibition. The reduced cortical inhibition observed in some neuropathologies could be influenced by reduced activity in specific excitatory neural populations. Including MEP latency assessment in research investigating SICI in clinical groups could assist in differentiating the cortical circuits impacted by neurological disorders.

Longitudinal assessment of 1H-MRS (GABA and Glx) and TMS measures of cortical inhibition and facilitation in the sensorimotor cortex.

The purpose of the present study was to investigate the long-term stability of water-referenced GABA and Glx neurometabolite concentrations in the sensorimotor cortex using MRS and to assess the long-term stability of GABA- and glutamate-related intracortical excitability using transcranial magnetic stimulation (TMS). Healthy individuals underwent two sessions of MRS and TMS at a 3-month interval. A MEGA-PRESS sequence was used at 3 T to acquire MRS signals in the sensorimotor cortex. Metabolites were quantified by basis spectra fitting and metabolite concentrations were derived using unsuppressed water reference scans accounting for relaxation and partial volume effects. TMS was performed using published standards. After performing stability and reliability analyses for MRS and TMS, reliable change indexes were computed for all measures with a statistically significant test-retest correlation. No significant effect of time was found for GABA, Glx and TMS measures. There was an excellent ICC and a strong correlation across time for GABA and Glx. Analysis of TMS measure stability revealed an excellent ICC for rMT CSP and %MSO and a fair ICC for 2 ms SICI. There was no significant correlation between MRS and TMS measures at any time point. This study shows that MRS-GABA and MRS-Glx of the sensorimotor cortex have good stability over a 3-month period, with variability across time comparable to that reported in other brain areas. While resting motor threshold, %MSO and CSP were found to be stable and reliable, other TMS measures had greater variability and lesser reliability.

Electrophysiological monitoring of inhibition in mammalian species, from rodents to humans.

GABAergic interneurons constitute a highly diverse family of neurons that play a critical role in cortical functions. Due to their prominent role in cortical network dynamics, genetic, developmental, or other dysfunctions in GABAergic neurons have been linked to neurological disorders such as epilepsy. Thus, it is crucial to investigate the interaction of these various neurons and to develop methods to specifically and directly monitor inhibitory activity in vivo. While research in small mammals has benefited from a wealth of recent technological development, bridging the gap to large mammals and humans remains a challenge. This is of particular interest since single neuron monitoring with intracranial electrodes in epileptic patients is developing quickly, opening new avenues for understanding the role of different cell types in epilepsy. Here, we review currently available techniques that monitor inhibitory activity in the brain and the respective validations in rodents. Finally, we discuss the future developments of these techniques and how knowledge from animal research can be translated to the study of neuronal circuit dynamics in the human brain.

Ensemble inhibition and excitation in the human cortex: An Ising-model analysis with uncertainties.

The pairwise maximum entropy model, also known as the Ising model, has been widely used to analyze the collective activity of neurons. However, controversy persists in the literature about seemingly inconsistent findings, whose significance is unclear due to lack of reliable error estimates. We therefore develop a method for accurately estimating parameter uncertainty based on random walks in parameter space using adaptive Markov-chain Monte Carlo after the convergence of the main optimization algorithm. We apply our method to the activity patterns of excitatory and inhibitory neurons recorded with multielectrode arrays in the human temporal cortex during the wake-sleep cycle. Our analysis shows that the Ising model captures neuronal collective behavior much better than the independent model during wakefulness, light sleep, and deep sleep when both excitatory (E) and inhibitory (I) neurons are modeled; ignoring the inhibitory effects of I neurons dramatically overestimates synchrony among E neurons. Furthermore, information-theoretic measures reveal that the Ising model explains about 80-95% of the correlations, depending on sleep state and neuron type. Thermodynamic measures show signatures of criticality, although we take this with a grain of salt as it may be merely a reflection of long-range neural correlations.

Assessment of motor cortex excitability and inhibition during a cognitive task in individuals with concussion.

PRIMARY OBJECTIVE: To examine the function of the motor cortex during executive function tasks in individuals with concussion, relative to healthy controls. METHODS AND PROCEDURES: Transcranial magnetic stimulation (TMS) was used to assess motor cortex excitability and inhibition acutely, within 72 hours, and over two months, post-concussion in 23 participants, nine individuals with concussion and 14 controls. Participants performed a cognitive task during TMS to determine the impact of cognitive task on the motor cortex. MAIN OUTCOMES AND RESULTS: Resting motor threshold (p = 0.02) and motor-evoked potential (MEPRest) amplitude (p = 0.03) were different between groups, both suggesting greater corticospinal excitability in individuals with concussion. Cortical silent period (CSP) duration was greater at 72 hours (p = 0.03), one month (p = 0.003) and two months (p = 0.05) in individuals with concussion, suggesting increased intracortical inhibition. The performance of a cognitive task caused an increase in MEPRest (p = 0.006) and CSP (p = 0.04), compared to baseline in both groups, but no interaction of condition by group (p ≥ 0.91) for either measure. CONCLUSION: Simultaneously performing a cognitive task during motor cortex assessments increased corticospinal excitability and intracortical inhibition; however, the increase was not different between groups.

Assessment of epilepsy using noninvasive visual psychophysics tests of surround suppression.

Powerful endogenous inhibitory mechanisms are thought to restrict the spread of epileptic discharges in cortical networks. Similar inhibitory mechanisms also influence physiological processing. We reasoned, therefore, that useful information about the quality of inhibitory restraint in individuals with epilepsy may be gleaned from psychophysical assays of these physiological processes. We derived a psychophysical measure of cortical inhibition, the motion surround suppression index (SSI), in 54 patients with epilepsy and 146 control subjects. Multivariate regression analyses showed that SSI was predicted strongly by age and seizure type, but not by seizure frequency. Specifically, we found that patients with exclusively focal epilepsy, and no history of generalization, showed significantly stronger cortical inhibition as measured by the SSI compared to all other groups, including controls. In contrast, patients with focal seizures evolving into generalized seizures, and patients with generalized genetic epilepsy, showed similar levels of cortical inhibition to controls. The presumptive focus, when one could be identified, was rarely found in visual cortex, meaning that the relationship with the epilepsy subtype is likely to reflect some global difference in inhibition in these subjects. This is the first reported instance of raised SSI in any patient cohort, and appears to differentiate between patients with respect to the likelihood of their experiencing generalization of their seizures. These results suggest that such simple psychophysical assays may provide useful aids to clinical management, particularly at the time of diagnosis.

Shared Neural Mechanisms for the Evaluation of Intense Sensory Stimulation and Economic Reward, Dependent on Stimulation-Seeking Behavior.

UNLABELLED: Why are some people strongly motivated by intense sensory experiences? Here we investigated how people encode the value of an intense sensory experience compared with economic reward, and how this varies according to stimulation-seeking preference. Specifically, we used a novel behavioral task in combination with computational modeling to derive the value individuals assigned to the opportunity to experience an intense tactile stimulus (mild electric shock). We then examined functional imaging data recorded during task performance to see how the opportunity to experience the sensory stimulus was encoded in stimulation-seekers versus stimulation-avoiders. We found that for individuals who positively sought out this kind of sensory stimulation, there was common encoding of anticipated economic and sensory rewards in the ventromedial prefrontal cortex. Conversely, there was robust encoding of the modeled probability of receiving such stimulation in the insula only in stimulation-avoidant individuals. Finally, we found preliminary evidence that sensory prediction error signals may be positively signed for stimulation-seekers, but negatively signed for stimulation-avoiders, in the posterior cingulate cortex. These findings may help explain why high intensity sensory experiences are appetitive for some individuals, but not for others, and may have relevance for the increased vulnerability for some psychopathologies, but perhaps increased resilience for others, in high sensation-seeking individuals. SIGNIFICANCE STATEMENT: People vary in their preference for intense sensory experiences. Here, we investigated how different individuals evaluate the prospect of an unusual sensory experience (electric shock), compared with the opportunity to gain a more traditional reward (money). We found that in a subset of individuals who sought out such unusual sensory stimulation, anticipation of the sensory outcome was encoded in the same way as that of monetary gain, in the ventromedial prefrontal cortex. Further understanding of stimulation-seeking behavior may shed light on the etiology of psychopathologies such as addiction, for which high or low sensation-seeking personality has been identified as a risk factor.

Social class affects Mu-suppression during action observation.

Socioeconomic status (SES) has been linked to differences in the degree to which people are attuned to others. Those who are lower in SES also tend to be more interpersonally attuned. However, to date, this work has not been demonstrated using neural measures. In the present electroencephalogram study, we found evidence that lower SES was linked to stronger Mu-suppression during action observation. This finding adds to the growing literature on factors that affect Mu-suppression and suggests that the mirror neuron system may be influenced by one's social class.

A paradigm of galvanic vestibular stimulation diminishes the soleus muscle H-reflex in healthy volunteers.

STUDY DESIGN: In this study, we explored how galvanic vestibular stimulation can modify the soleus H-reflex (Hoffman reflex), that is, the excitability of the spinal cord circuits, in healthy humans. OBJECTIVES: Our aim was to demonstrate H-reflex amplitude modulation caused by changing the duration and the intensity of the anodal galvanic vestibular stimulation. Therefore, we measured H-reflex before and after applied vestibular stimulation. SETTINGS: This study was conducted in Rehabilitation Clinic, Belgrade, Serbia. METHODS: The measurements were performed on 5 male volunteers aged 22-30 years. Anodal galvanic stimulation was applied on the right mastoid in prone position. H-reflex was elicited by nervus tibialis stimulation and measured from the right soleus muscle. In three subjects, trains of weak and strong galvanic stimuli (1, 5 and 9) were applied. In two subjects, only a train of 9 strong stimuli was applied. RESULTS: A statistically significant decrease of the H-reflex amplitude after anodal galvanic stimulation was demonstrated in all subjects. The percentage of H-reflex amplitude diminution was between 6 and 18 in subjects with weak and strong stimuli and 5 and 6 in subjects with only 9 strong stimuli. CONCLUSION: We intend to use this paradigm of stimulation to explore whether the vestibulospinal function exists after spinal cord injury (SCI). If it exists, it can be used to influence the preserved spinal cord circuits after SCI. SPONSORSHIP: One of the authors (Nadica Miljkovic) was partly supported by the Ministry of education, science and technological development, Republic of Serbia, grant OS175016.

Revealing cell assemblies at multiple levels of granularity.

BACKGROUND: Current neuronal monitoring techniques, such as calcium imaging and multi-electrode arrays, enable recordings of spiking activity from hundreds of neurons simultaneously. Of primary importance in systems neuroscience is the identification of cell assemblies: groups of neurons that cooperate in some form within the recorded population. NEW METHOD: We introduce a simple, integrated framework for the detection of cell-assemblies from spiking data without a priori assumptions about the size or number of groups present. We define a biophysically-inspired measure to extract a directed functional connectivity matrix between both excitatory and inhibitory neurons based on their spiking history. The resulting network representation is analyzed using the Markov Stability framework, a graph theoretical method for community detection across scales, to reveal groups of neurons that are significantly related in the recorded time-series at different levels of granularity. RESULTS AND COMPARISON WITH EXISTING METHODS: Using synthetic spike-trains, including simulated data from leaky-integrate-and-fire networks, our method is able to identify important patterns in the data such as hierarchical structure that are missed by other standard methods. We further apply the method to experimental data from retinal ganglion cells of mouse and salamander, in which we identify cell-groups that correspond to known functional types, and to hippocampal recordings from rats exploring a linear track, where we detect place cells with high fidelity. CONCLUSIONS: We present a versatile method to detect neural assemblies in spiking data applicable across a spectrum of relevant scales that contributes to understanding spatio-temporal information gathered from systems neuroscience experiments.

Computer-automated tinnitus assessment: noise-band matching, maskability, and residual inhibition.

BACKGROUND: Psychoacoustic measures of tinnitus typically include loudness and pitch match, minimum masking level (MML), and residual inhibition (RI). We previously developed and documented a computer-automated tinnitus evaluation system (TES) capable of subject-guided loudness and pitch matching. The TES was further developed to conduct computer-aided, subject-guided testing for noise-band matching (NBM), MML, and RI. PURPOSE: The purpose of the present study was to document the capability of the upgraded TES to obtain measures of NBM, MML, and RI, and to determine the test-retest reliability of the responses obtained. RESEARCH DESIGN: Three subject-guided, computer-automated testing protocols were developed to conduct NBM. For MML and RI testing, a 2-12 kHz band of noise was used. All testing was repeated during a second session. STUDY SAMPLE: Subjects meeting study criteria were selected from those who had previously been tested for loudness and pitch matching in our laboratory. A total of 21 subjects completed testing, including seven females and 14 males. RESULTS: The upgraded TES was found to be fairly time efficient. Subjects were generally reliable, both within and between sessions, with respect to the type of stimulus they chose as the best match to their tinnitus. Matching to bandwidth was more variable between measurements, with greater consistency seen for subjects reporting tonal tinnitus or wide-band noisy tinnitus than intermediate types. Between-session repeated MMLs were within 10 dB of each other for all but three of the subjects. Subjects who experienced RI during Session 1 tended to be those who experienced it during Session 2. CONCLUSIONS: This study may represent the first time that NBM, MML, and RI audiometric testing results have been obtained entirely through a self-contained, computer-automated system designed specifically for use in the clinic. Future plans include refinements to achieve greater testing efficiency.

Design and rationale of studies of neurohormonal blockade and outcomes in diastolic heart failure using OPTIMIZE-HF registry linked to Medicare data.

BACKGROUND: Heart failure (HF) is the leading cause of hospitalization for Medicare beneficiaries. Nearly half of all HF patients have diastolic HF or HF with preserved ejection fraction (HF-PEF). Because these patients were excluded from major randomized clinical trials of neurohormonal blockade in HF there is little evidence about their role in HF-PEF. METHODS: The aims of the American Recovery & Reinvestment Act-funded National Heart, Lung, and Blood Institute-sponsored "Neurohormonal Blockade and Outcomes in Diastolic Heart Failure" are to study the long-term effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists in four separate propensity-matched populations of HF-PEF patients in the OPTIMIZE-HF (Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure) registry. Of the 48,612 OPTIMIZE-HF hospitalizations occurring during 2003-2004 in 259 U.S. hospitals, 20,839 were due to HF-PEF (EF ≥40%). For mortality and hospitalization we used Medicare national claims data through December 31, 2008. RESULTS: Using a two-step (hospital-level and hospitalization-level) probabilistic linking approach, we assembled a cohort of 11,997 HF-PEF patients from 238 OPTIMIZE-HF hospitals. These patients had a mean age of 75 years, mean EF of 55%, were 62% women, 15% African American, and were comparable with community-based HF-PEF cohorts in key baseline characteristics. CONCLUSIONS: The assembled Medicare-linked OPTIMIZE-HF cohort of Medicare beneficiaries with HF-PEF with long-term outcomes data will provide unique opportunities to study clinical effectivenss of various neurohormonal antagonists with outcomes in HF-PEF using propensity-matched designs that allow outcome-blinded assembly of balanced cohorts, a key feature of randomized clinical trials.

Task-switching in oculomotor control: unidirectional switch-cost when alternating between pro- and antisaccades.

The antisaccade task requires the suppression of a reflexive prosaccade (i.e., response suppression) and the remapping of a target location to mirror-symmetrical space (i.e., vector inversion). Moreover, antisaccades are associated with increased activation of cortical oculomotor networks: a finding attributed to the top-down requirements of response suppression and vector inversion. The goal of the present study was to determine if the increased cortical activity associated with antisaccades elicits a residual inhibition of oculomotor planning networks. To that end, each trial in this investigation entailed the onset of a single and exogenously presented target (i.e., archetypical antisaccade task) and participants were instructed to alternate between pro- and antisaccades in blocked and random task-switching schedules. In the blocked schedule, the saccade tasks (i.e., pro- and antisaccades) alternated on every second trial (AABB paradigm) whereas in the random schedule the saccade tasks were pseudo-randomly interleaved on a trial-by-trial basis. Reaction times for task-switch prosaccades were longer and more variable than their task-repetition counterparts, whereas antisaccades did not vary as a function of task-switch and task-repetition trials: a finding that was consistent across blocked and random presentation schedules. In other words, results demonstrate a unidirectional switch-cost for prosaccades. As such, we propose that the top-down processes required to complete an antisaccade results in residual inhibition of oculomotor networks supporting a subsequent prosaccade.

Assessment of post-excitatory long-interval cortical inhibition in adult attention-deficit/hyperactivity disorder.

In order to further examine cortical impairment in adult ADHD patients and to test the hypothesis of a disturbed neuronal inhibition in adults with ADHD, late auditory evoked potentials were measured. By using paired-chirp auditory late responses, we compared 15 adults with ADHD with 15 control subjects, focusing on the inhibition elicited by the stimuli. Besides amplitude measurements, a time-frequency phase coherence study using the wavelet phase synchronization stability (WPSS) was performed. ADHD was diagnosed according to DSM-IV criteria. All ADHD subjects were without medication and did not suffer from any further axis I disorder. WPSS analysis revealed impaired auditory inhibition for ADHD patients for interstimulus intervals (ISI) between 500 and 1,100 ms as compared with healthy controls. By analyzing the WPSS in the interval from 80 ms to 220 ms, mean inhibition of the test chirp was found to be 6% in the ADHD group and 38.5% in the control subjects (p = 0.01). Moreover, overall smaller amplitudes in the N100 and P200 waves at all ISI were found (p = 0.04 and p = 0.02). However, reproducibility indices in the amplitude measurements were low, thus supporting the use of the instantaneous phase-based analysis method. The results support the hypothesis of reduced intracortical inhibition as a correlate of disturbed brain function in adults with ADHD.

A Markovian event-based framework for stochastic spiking neural networks.

In spiking neural networks, the information is conveyed by the spike times, that depend on the intrinsic dynamics of each neuron, the input they receive and on the connections between neurons. In this article we study the Markovian nature of the sequence of spike times in stochastic neural networks, and in particular the ability to deduce from a spike train the next spike time, and therefore produce a description of the network activity only based on the spike times regardless of the membrane potential process. To study this question in a rigorous manner, we introduce and study an event-based description of networks of noisy integrate-and-fire neurons, i.e. that is based on the computation of the spike times. We show that the firing times of the neurons in the networks constitute a Markov chain, whose transition probability is related to the probability distribution of the interspike interval of the neurons in the network. In the cases where the Markovian model can be developed, the transition probability is explicitly derived in such classical cases of neural networks as the linear integrate-and-fire neuron models with excitatory and inhibitory interactions, for different types of synapses, possibly featuring noisy synaptic integration, transmission delays and absolute and relative refractory period. This covers most of the cases that have been investigated in the event-based description of spiking deterministic neural networks.

The incidence and management of tolerance in intrathecal baclofen therapy.

STUDY DESIGN: Retrospective study. OBJECTIVES: To study the incidence and management of tolerance in patients treated with intrathecal baclofen (ITB) therapy. SETTING: Department of neurology and neurosurgery, University Medical Center Groningen, The Netherlands. METHODS: Medical records of all patients who had received an implantable ITB pump at our clinic during 1991-2005 were reviewed. RESULTS: A total of 37 patients (representing 116 pump years) were included. Mean follow-up time was 38 months (range 3-120 months). Baclofen dose increased in the first 18 months after implantation (P<0.05), and then stabilized around a mean dose of 350 microg per day. Eight patients (22%) developed tolerance, defined as a dose increase of >100 microg per year. No predictive factors for development of tolerance could be determined. Three different treatment regimens for tolerant patients were analyzed. Altering the infusion mode from simple to complex continuous (n=6) had no effect on the development of tolerance. Pulsatile bolus infusion (n=1) and a drug holiday (n=2) were both effective in reducing the daily baclofen dose. Patients who needed surgical revision of the pump system because of mechanical failures (n=11) showed a significant dose decrease during the first month after revision, indicating that the preoperative dose increase most likely had been caused by the pump failure. Pump-related complications occurred once per 10.5 years of ITB treatment. Drug-related side effects had an annual risk of 13.8%. The reported events were mostly mild. CONCLUSIONS: ITB therapy is effective and safe, also in the long term and causes tolerance in only 22% of the treated patients.

A first-order nonhomogeneous Markov model for the response of spiking neurons stimulated by small phase-continuous signals.

We present a first-order nonhomogeneous Markov model for the interspike-interval density of a continuously stimulated spiking neuron. The model allows the conditional interspike-interval density and the stationary interspike-interval density to be expressed as products of two separate functions, one of which describes only the neuron characteristics and the other of which describes only the signal characteristics. The approximation shows particularly clearly that signal autocorrelations and cross-correlations arise as natural features of the interspike-interval density and are particularly clear for small signals and moderate noise. We show that this model simplifies the design of spiking neuron cross-correlation systems and describe a four-neuron mutual inhibition network that generates a cross-correlation output for two input signals.