Event-related brain potential correlates of human auditory sensory memory-trace formation

The event-related potential (ERP) component mismatch negativity (MMN) is a neural marker of human echoic memory. MMN is elicited by deviant sounds embedded in a stream of frequent standards, reflecting the deviation from an inferred memory trace of the standard stimulus. The strength of this memory trace is thought to be proportional to the number of repetitions of the standard tone, visible as the progressive enhancement of MMN with number of repetitions (MMN memory-trace effect). However, no direct ERP correlates of the formation of echoic memory traces are currently known. This study set out to investigate changes in ERPs to different numbers of repetitions of standards, delivered in a roving-stimulus paradigm in which the frequency of the standard stimulus changed randomly between stimulus trains. Normal healthy volunteers (n = 40) were engaged in two experimental conditions: during passive listening and while actively discriminating changes in tone frequency. As predicted, MMN increased with increasing number of standards. However, this MMN memory-trace effect was caused mainly by enhancement with stimulus repetition of a slow positive wave from 50 to 250 ms poststimulus in the standard ERP, which is termed here "repetition positivity" (RP). This RP was recorded from frontocentral electrodes when participants were passively listening to or actively discriminating changes in tone frequency. RP may represent a human ERP correlate of rapid and stimulus-specific adaptation, a candidate neuronal mechanism underlying sensory memory formation in the auditory cortex

Cabergoline reduces 3-methoxytyramine in a SDHC patient with metastatic paraganglioma and prolactinoma.

Summary: We observed a novel therapeutic response with cabergoline in a male patient with a dopamine-secreting head and neck paraganglioma (HNPGL), macroprolactinoma and germline succinate dehydrogenase C mutation (SDHC). The macroprolactinoma was treated with cabergoline which gave an excellent response. He was found to have raised plasma 3-methoxytyramine of 1014 pmol/L (NR: 0-180 pmol/L); but it was unclear if this was a drug-induced phenomenon from dopamine agonist (DA) therapy. Cabergoline was stopped for 4 weeks and the 3-methoxytyramine level increased significantly to 2185 pmol/L, suggesting a biochemical response of his HNPGL. Subsequently, Gallium-68 Dotatate PET and MRI (Gallium-68 Dotatate PET/MRI) demonstrated a second lesion in the sacrum. Both the HNPGL and metastatic sacral deposit received external beam radiotherapy with a good biochemical and radiological response. Conclusion: Our case report highlights the rare potential of germline SDHC mutations causing metastatic paraganglioma and concurrent pituitary tumours. Cabergoline treatment may lower elevated 3-methoxytyramine levels and, therefore, mask the biochemical evidence of metastatic disease but also may have therapeutic relevance in dopamine-secreting pheochromocytomas/paragangliomas (PPGLs). Learning points: Several neuroendocrine tumours (NETs) express dopamine D2 and D4 receptors. In this case report, cabergoline significantly reduced plasma 3-methoxytyramine level in a patient with functional HNPGL. Cabergoline might have therapeutic relevance in dopamine-secreting PPGLs. Paragangliomas associated with SDHC mutation classically present with asymptomatic non-functional HNPGL and have rare metastatic potential. The association of pheochromocytoma or paraganglioma and pituitary adenoma is now a well-described rare association (<1%), designated as the three P association. While the three P association is most commonly seen with succinate dehydrogenase B and D mutations, it has also been described in patients with SDHA and SDHC mutations. Cabergoline treatment may lower elevated 3-methoxytyramine levels and mask the biochemical evidence of metastatic disease. Regular functional imaging with Gallium-68 Dotatate PET/MRI provides better evidence of metastatic disease

Network dynamics in the healthy and epileptic developing brain

Electroencephalography (EEG) allows recording of cortical activity at high temporal resolution. EEG recordings can be summarised along different dimensions using network-level quantitative measures, e.g. channel-to-channel correlation, or band power distributions across channels. These reveal network patterns that unfold over a range of different time scales and can be tracked dynamically. Here we describe the dynamics of network-state transitions in EEG recordings of spontaneous brain activity in normally developing infants and infants with severe early infantile epileptic encephalopathies (n=8, age: 1-8 months). We describe differences in measures of EEG dynamics derived from band power, and correlation-based summaries of network-wide brain activity. We further show that EEGs from different patient groups and controls may be distinguishable based on a small set of the novel quantitative measures introduced here, which describe dynamic network state switching. Quantitative measures related to the sharpness of switching from one correlation pattern to another show the largest differences between groups. These findings reveal that the early epileptic encephalopathies are associated with characteristic dynamic features at the network level. Quantitative network-based analyses like the one presented here may in future inform the clinical use of quantitative EEG for diagnosis

The Pair Test: A computerised measure of learning and memory

There is increasing interest in the assessment of learning and memory in typically developing children as well as in children with neurodevelopmental disorders. However, neuropsychological assessments have been hampered by the dearth of standardised tests that enable direct comparison between distinct memory processes or between types of stimulus materials. We developed a tablet-based paired-associate learning paradigm, the Pair Test, based on neurocognitive models of learning and memory. The aims are to (i) establish the utility of this novel memory tool for use with children across a wide age range, and (ii) examine test validity, reliability and reproducibility of the construct. The convergent validity of the test was found to be adequate, and higher test reliability was shown for the Pair Test compared to standardised measures. Moderate test-retest reproducibility was shown, despite a long time interval between sessions (14 months). Moreover, the Pair Test is able to capture developmental changes in memory, and can therefore chart the developmental trajectory of memory and learning functions across childhood and adolescence. Finally, we used this novel instrument to acquire normative data from 130 typically developing children, aged 8-18 years. Age-stratified normative data are provided for learning, delayed recall and delayed recognition, for measures of verbal and non-verbal memory. The Pair Test thus provides measures of learning and memory accounting for encoding, consolidation and retrieval processes. As such, the standardised test results can be used to determine the status of learning and memory in healthy children, and also to identify deficits in paediatric patients at risk of damage to the neural network underlying mnemonic functions

INTERPRETATION OF P300 AMPLITUDE CHANGES BY THE USE OF ADAPTATION LEVEL THEORY

Commentary on Rolf Verleger (1988). Event-related potentials and cognition: A critique of the context updating hypothesis and an alternative interpretation of P3. BBS 11: 343–427

Mismatch negativity indexes illness-specific impairments of cortical plasticity in schizophrenia: a comparison with bipolar disorder and Alzheimer's disease.

Cognitive impairment is an important predictor of functional outcome in patients with schizophrenia, yet its neurobiology is still incompletely understood. Neuropathological evidence of impaired synaptic connectivity and NMDA receptor-dependent transmission in superior temporal cortex motivated us to explore the correlation of in vivo mismatch negativity (MMN) with cognitive status in patients with schizophrenia. MMN elicited in a roving stimulus paradigm displayed a response proportional to the number of stimulus repetitions (memory trace effect). Preliminary evidence in patients with chronic schizophrenia suggests that attenuation of this MMN memory trace effect was correlated with the degree of neuropsychological memory dysfunction. Here we present data from a larger confirmatory study in patients with schizophrenia, bipolar disorder, probable Alzheimer's disease and healthy controls. We observed that the diminution of the MMN memory trace effect and its correlation with memory impairment was only found in the schizophrenia group. Recent pharmacological studies using the roving paradigm suggest that attenuation of the MMN trace effect can be understood as abnormal modulation of NMDA receptor-dependent plasticity. We suggest that the convergence of the previously identified synaptic pathology in supragranular cortical layers with the intracortical locus of MMN generation accounts for the remarkable robustness of MMN impairments in schizophrenia. We further speculate that this layer-specific synaptic pathology identified in supragranular neurons plays a pivotal computational role, by weakening the encoding and propagation of prediction errors to higher cortical modules. According to predictive coding theory such breakdown will have grave implications not only for perception, but also for higher-order cognition and may thus account for the MMN-cognition correlations observed here. Finally, MMN is a sensitive and specific biomarker for detecting the early prodromal phase of schizophrenia and is well suited for the exploration of novel cognition-enhancing agents in humans

A Functional MRI Paradigm Suitable for Language and Memory Mapping in Pediatric Temporal Lobe Epilepsy

Functional Magnetic Resonance Imaging (fMRI) is a technique frequently used to determine the territories of eloquent tissue that serve critical functions, such as language. This can be particularly useful as part of the pre-surgical assessment for temporal lobe epilepsy (TLE) in order to predict cognitive outcome and guide surgical decision-making. Whereas language fMRI is widely used, memory fMRI is less frequently employed in adult TLE, and lacking in childhood TLE. We have developed a combined language/memory fMRI paradigm that is suitable for children, to provide clinically useful information for surgical planning in pediatric TLE. We evaluated this paradigm in 28 healthy children, aged 8 to 18 years. The advantages of this paradigm are: (a) it examines the functional mapping of language and memory networks within one scanning session, (b) provides assessment of both memory encoding- and retrieval-related neural networks, (c) examines recall-based retrieval to engage hippocampal involvement compared to recognition-based retrieval, and (d) provides overt verbal responses to monitor in-scanner memory performance. This novel fMRI paradigm was designed for language and memory mapping in pediatric TLE and could provide clinically useful information for surgical planning. Finally, parallel versions of the paradigm allow the comparison of brain activations pre- and post-surgical intervention

Memory in paediatric temporal lobe epilepsy: effects of lesion type and side.

This study investigated the role of underlying pathology on memory function of children with temporal lobe epilepsy (TLE). Memory was assessed in 44 children with TLE resulting from hippocampal sclerosis (HS) or dysembryoplastic neuroepithelial tumours (DNT), and 22 control children. Delayed story and paired associate recall performance was significantly more impaired in children with HS compared to those with DNT, irrespective of the affected side. Semantic memory was impaired in both HS groups, and also in the left DNT group. These results suggest a role for type, and to a lesser extent, side of pathology in the memory profile of children with TLE

Gamma and beta frequency oscillations in response to novel auditory stimuli: A comparison of human electroencephalogram (EEG) data with in vitro models

Investigations using hippocampal slices maintained in vitro have demonstrated that bursts of oscillatory field potentials in the gamma frequency range (30-80 Hz) are followed by a slower oscillation in the beta 1 range (12-20 Hz). In this study, we demonstrate that a comparable gamma-to-beta transition is seen in the human electroencephalogram (EEG) in response to novel auditory stimuli. Correlations between gamma and beta 1 activity revealed a high degree of interdependence of synchronized oscillations in these bands in the human EEG. Evoked (stimulus-locked) gamma oscillations preceded beta 1 oscillations in response to novel stimuli, suggesting that this may be analogous to the gamma-to-beta shift observed in vitro. Beta 1 oscillations were the earliest discriminatory responses to show enhancement to novel stimuli, preceding changes in the broad-band event-related potential (mismatch negativity). Later peaks of induced beta activity over the parietal cortex were always accompanied by an underlying gamma frequency oscillation as seen in vitro. A further analogy between in vitro and human recordings was that both gamma and beta oscillations habituated markedly after the initial novel stimulus presentation

Interictal epileptiform discharges have an independent association with cognitive impairment in children with lesional epilepsy

OBJECTIVES: The relative contribution of interictal epileptiform discharges (IEDs) to cognitive dysfunction in comparison with the underlying brain pathology is not yet understood in children with lesional focal epilepsy. METHODS: The current study investigated the association of IEDs with intellectual functioning in 103 children with medication-resistant focal epilepsy. Hierarchical multiple regression analyses were used to determine the independent contribution of IED features on intellectual functioning, after controlling for effects of lesional pathology, epilepsy duration, and medication. Exploratory analyses were conducted for language and memory scores as well as academic skills available in a subset of participants. RESULTS: The results reveal that IEDs have a negative association with IQ with independent, additive effects documented for frequent and bilaterally distributed IEDs as well as discharge enhancement in sleep. Left-lateralized IEDs had a prominent effect on verbal intelligence, in excess of the influence of left-sided brain pathology. These effects extended to other cognitive functions, most prominently for sleep-enhanced IEDs to be associated with deficits in expressive and receptive language, reading, spelling and numerical skills. SIGNIFICANCE: Overall, IED effects on cognition were of a magnitude similar to lesional influences or drug effects (topiramate use). This study demonstrates an association between IEDs and cognitive dysfunction, independent of the underlying focal brain pathology