Torsten Baldeweg

Synaptic Plasticity and Dysconnection in Schizophrenia

Current pathophysiological theories of schizophrenia highlight the role of altered brain connectivity. This dysconnectivity could manifest 1) anatomically, through structural changes of association fibers at the cellular level, and/or 2) functionally, through aberrant control of synaptic plasticity at the synaptic level. In this article, we review the evidence for these theories, focusing on the modulation of synaptic plasticity. In particular, we discuss how dysconnectivity, observed between brain regions in schizophrenic patients, could result from abnormal modulation of N-methyl-D-aspartate (NMDA)-dependent plasticity by other neurotransmitter systems. We focus on the implication of the dysconnection hypothesis for functional imaging at the systems level. In particular, we review recent advances in measuring plasticity in the human brain using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) that can be used to address dysconnectivity in schizophrenia. Promising experimental paradigms include perceptual and reinforcement learning. We describe how theoretical and causal models of brain responses might contribute to a mechanistic understanding of synaptic plasticity in schizophrenia.

A Possible Role for Gap Junctions in Generation of Very Fast EEG Oscillations Preceding the Onset of, and Perhaps Initiating, Seizures

Summary:  Purpose: We propose an experimentally and clinically testable hypothesis, concerning the origin of very fast (>∼70 Hz) EEG oscillations that sometimes precede the onset of focal seizures. These oscillations are important, as they may play a causal role in the initiation of seizures.

Language fMRI abnormalities associated with FOXP2 gene mutation.

Half the members of the KE family suffer from a speech and language disorder caused by a mutation in the FOXP2 gene. We examined functional brain abnormalities associated with this mutation using two fMRI language experiments, one involving covert (silent) verb generation and the other overt (spoken) verb generation and word repetition. The unaffected family members showed a typical left-dominant distribution of activation involving Brocas area in the generation tasks and a more bilateral distribution in the repetition task, whereas the affected members showed a more posterior and more extensively bilateral pattern of activation in all tasks. Consistent with previously reported bilateral morphological abnormalities, the affected members showed significant underactivation relative to the unaffected members in Brocas area and its right homolog, as well as in other cortical language-related regions and in the putamen. Our findings suggest that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language.

The mismatch negativity (MMN) - A unique window to disturbed central auditory processing in ageing and different clinical conditions

In this article, we review clinical research using the mismatch negativity (MMN), a change-detection response of the brain elicited even in the absence of attention or behavioural task. In these studies, the MMN was usually elicited by employing occasional frequency, duration or speech-sound changes in repetitive background stimulation while the patient was reading or watching videos. It was found that in a large number of different neuropsychiatric, neurological and neurodevelopmental disorders, as well as in normal ageing, the MMN amplitude was attenuated and peak latency prolonged. Besides indexing decreased discrimination accuracy, these effects may also reflect, depending on the specific stimulus paradigm used, decreased sensory-memory duration, abnormal perception or attention control or, most importantly, cognitive decline. In fact, MMN deficiency appears to index cognitive decline irrespective of the specific symptomatologies and aetiologies of the different disorders involved.

The functional anatomy of the MMN: A DCM study of the roving paradigm

Using dynamic causal modelling (DCM), we have presented provisional evidence to suggest: (i) the mismatch negativity (MMN) is generated by self-organised interactions within a hierarchy of cortical sources [Garrido, M.I., Kilner, J.M., Kiebel, S.J., Stephan, K.E., Friston, K.J., 2007. Dynamic causal modelling of evoked potentials: a reproducibility study. NeuroImage 36, 571-580] and (ii) the MMN rests on plastic change in both extrinsic (between-source) and intrinsic (within source) connections (Garrido et al., under review). In this work we re-visit these two key issues in the context of the roving paradigm. Critically, this paradigm allows us to discount any differential response to differences in the stimuli per se, because the standards and oddballs are physically identical. We were able to confirm both the hierarchical nature of the MMN generation and the conjoint role of changes in extrinsic and intrinsic connections. These findings are consistent with a predictive coding account of repetition-suppression and the MMN, which gracefully accommodates two important mechanistic perspectives; the model-adjustment hypothesis [Winkler, I., Karmos, G., Näätänen, R., 1996. Adaptive modelling of the unattended acoustic environment reflected in the mismatch negativity event-related potential. Brain Res. 742, 239-252; Näätänen, R., Winkler, I., 1999. The concept of auditory stimulus representation in cognitive neuroscience. Psychol Bull 125, 826-859; Sussman, E., Winkler, I., 2001. Dynamic sensory updating in the auditory system. Brain Res. Cogn Brain Res. 12, 431-439] and the adaptation hypothesis [May, P., Tiitinen, H., Ilmoniemi, R.J., Nyman, G., Taylor, J.G., Näätänen, R., 1999. Frequency change detection in human auditory cortex. J. Comput. Neurosci. 6, 99-120; Jääskeläinen, I.P., Ahveninen, J., Bonmassar, G., Dale, A.M., Ilmoniemi, R.J., Levänen, S., Lin, F.H., May, P., Melcher, J., Stufflebeam, S., Tiitinen, H., Belliveau, J.W., 2004. Human posterior auditory cortex gates novel sounds to consciousness. Proc. Natl. Acad. Sci. U. S. A. 101, 6809-6814].

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.

Axonal Gap Junctions Between Principal Neurons: A Novel Source of Network Oscillations, and Perhaps Epileptogenesis

We hypothesized in 1998 that gap junctions might be located between the axons of principal hippocampal neurons, based on the shape of spikelets (fast prepotentials), occurring during gap junction-mediated very fast (to approximately 200 Hz) network oscillations in vitro. More recent electrophysiological, pharmacological and dye-coupling data indicate that axonal gap junctions exist; so far, they appear to be located about 100 microm from the soma, in CA1 pyramidal neurons. Computer modeling and theory predict that axonal gap junctions can lead to very fast network oscillations under three conditions: a) there are spontaneous axonal action potentials; b) the number of gap junctions in the network is neither too low (not less than to approximately 1.5 per cell on average), nor too high (not more than to approximately 3 per cell on average); c) action potentials can cross from axon to axon via gap junctions. Simulated oscillations resemble biological ones, but condition (c) remains to be demonstrated directly. Axonal network oscillations can, in turn, induce oscillatory activity in larger neuronal networks, by a variety of mechanisms. Axonal networks appear to underlie in vivo ripples (to approximately 200 Hz field potential oscillations superimposed on physiological sharp waves), to drive gamma (30-70 Hz) oscillations that appear in the presence of carbachol, and to initiate certain types of ictal discharge. If axonal gap junctions are important for seizure initiation in humans, there could be practical consequences for antiepileptic therapy: at least one gap junction-blocking compound, carbenoxolone, is already in clinical use (for treatment of ulcer disease), and it crosses the blood-brain barrier.

The mismatch negativity: an index of cognitive decline in neuropsychiatric and neurological diseases and in ageing

Cognitive impairment is a core element shared by a large number of different neurological and neuropsychiatric diseases. Irrespective of their different aetiologies and symptomatologies, most appear to converge at the functional deficiency of the auditory-frontal cortex network of auditory discrimination, which indexes cognitive impairment shared by these abnormalities. This auditory-frontal cortical deficiency, and hence cognitive decline, can now be objectively measured with the mismatch negativity and its magnetic equivalent. The auditory-frontal cortical network involved seems, therefore, to play a pivotal, unifying role in the different abnormalities. It is, however, more likely that the dysfunction that can be detected with the mismatch negativity and its magnetoencephalographic equivalent manifests a more widespread brain disorder, namely, a deficient N-methyl-D-aspartate receptor function, shared by these abnormalities and accounting for most of the cognitive decline.

Repetition effects to sounds: evidence for predictive coding in the auditory system

Grill-Spector, Henson and Martin [1] recently reviewed evidence for neural repetition effects in the visual system. They discussed models that account for behavioural facilitation and reduced neural activity after stimulus repetition (‘repetition suppression’), measured using single-unit recording and human ERP and fMRI. Here I discuss studies that support and extend such effects to audition.

The Development of Intellectual Abilities in Pediatric Temporal Lobe Epilepsy

Summary:  Purpose: The aim of this study was to examine the impact of clinical variables, particularly age at onset of epilepsy, on intellectual function in a group of children with temporal lobe epilepsy (TLE).