Klaus Funke

Effect of transcranial magnetic stimulation on single-unit activity in the cat primary visual cortex

Transcranial magnetic stimulation (TMS) has become a well established procedure for testing and modulating the neuronal excitability of human brain areas, but relatively little is known about the cellular processes induced by this rather coarse stimulus. In a first attempt, we performed extracellular single‐unit recordings in the primary visual cortex (area 17) of the anaesthetised and paralysed cat, with the stimulating magnetic field centred at the recording site (2 × 70 mm figure‐of‐eight coil). The effect of single biphasic TMS pulses, which induce a lateral‐to‐medial electric current within the occipital pole of the right hemisphere, was tested for spontaneous as well as visually evoked activity. For cat visual cortex we found that a single TMS pulse elicited distinct episodes of enhanced and suppressed activity: in general, a facilitation of activity was found during the first 500 ms, followed thereafter by a suppression of activity lasting up to a few seconds. Strong stimuli exceeding 50 % of maximal stimulator output could also lead to an early suppression of activity during the first 100–200 ms, followed by stronger (rebound) facilitation. Early suppression and facilitation of activity may be related to a more or less direct stimulation of inhibitory and excitatory interneurons, probably with different thresholds. The late, long‐lasting suppression is more likely to be related to metabotropic or metabolic processes, or even vascular responses. The time course of facilitation/inhibition may provide clues regarding the action of repetitive TMS application.

State-dependent receptive-field restructuring in the visual cortex.

To extract important information from the environment on a useful timescale, the visual system must be able to adapt rapidly to constantly changing scenes. This requires dynamic control of visual resolution, possibly at the level of the responses of single neurons. Individual cells in the visual cortex respond to light stimuli on particular locations (receptive fields) on the retina, and the structure of these receptive fields can change in different contexts. Here we show experimentally that the shape of receptive fields in the primary visual cortex of anaesthetized cats undergoes significant modifications, which are correlated with the general state of the brain as assessed by electroencephalography: receptive fields are wider during synchronized states and smaller during non-synchronized states. We also show that cortical receptive fields shrink over time when stimulated with flashing light spots. Finally, by using a network model we account for the changing size of the cortical receptive fields by dynamically rescaling the levels of excitation and inhibition in the visual thalamus and cortex. The observed dynamic changes in the sizes of the cortical receptive field could be a reflection of a process that adapts the spatial resolution within the primary visual pathway to different states of excitability.

Theta-Burst Transcranial Magnetic Stimulation Alters Cortical Inhibition

Human cortical excitability can be modified by repetitive transcranial magnetic stimulation (rTMS), but the cellular mechanisms are largely unknown. Here, we show that the pattern of delivery of theta-burst stimulation (TBS) (continuous versus intermittent) differently modifies electric activity and protein expression in the rat neocortex. Intermittent TBS (iTBS), but not continuous TBS (cTBS), enhanced spontaneous neuronal firing and EEG gamma band power. Sensory evoked cortical inhibition increased only after iTBS, although both TBS protocols increased the first sensory response arising from the resting cortical state. Changes in the cortical expression of the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB) indicate that changes in spontaneous and evoked cortical activity following rTMS are in part related to altered activity of inhibitory systems. By reducing PV expression in the fast-spiking interneurons, iTBS primarily affected the inhibitory control of pyramidal cell output activity, while cTBS, by reducing CB expression, more likely affected the dendritic integration of synaptic inputs controlled by other classes of inhibitory interneurons. Calretinin, the third major calcium-binding protein expressed by another class of interneurons was not affected at all. We conclude that different patterns of TBS modulate the activity of inhibitory cell classes differently, probably depending on the synaptic connectivity and the preferred discharge pattern of these inhibitory neurons.

Modulation of cortical inhibition by rTMS – findings obtained from animal models

Abstract  Transcranial magnetic stimulation (TMS) has become a popular method to non‐invasively stimulate the human brain. The opportunity to modify cortical excitability with repetitive stimulation (rTMS) has especially gained interest for its therapeutic potential. However, details of the cellular mechanisms of the effects of rTMS are scarce. Currently favoured are long‐term changes in the efficiency of excitatory synaptic transmission, with low‐frequency rTMS depressing it, but high‐frequency rTMS augmenting. Only recently has modulation of cortical inhibition been considered as an alternative way to explain lasting changes in cortical excitability induced by rTMS. Adequate animal models help to highlight stimulation‐induced changes in cellular processes which are not assessable in human rTMS studies. In this review article, we summarize findings obtained with our rat models which indicate that distinct inhibitory cell classes, like the fast‐spiking cells characterized by parvalbumin expression, are most sensitive to certain stimulation protocols, e.g. intermittent theta burst stimulation. We discuss how our findings can support the recently suggested models of gating and homeostatic plasticity as possible mechanisms of rTMS‐induced changes in cortical excitability.

Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects

BACKGROUND/OBJECTIVES Over the last ten years, an increasing number of authors have used the theta burst stimulation (TBS) protocol to investigate long-term potentiation (LTP) and long-term depression (LTD)-like plasticity non-invasively in the primary motor cortex (M1) in healthy humans and in patients with various types of movement disorders. We here provide a comprehensive review of the LTP/LTD-like plasticity induced by TBS in the human M1. METHODS A workgroup of researchers expert in this research field review and discuss critically ten years of experimental evidence from TBS studies in humans and in animal models. The review also includes the discussion of studies assessing responses to TBS in patients with movement disorders. MAIN FINDINGS/DISCUSSION We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various neurological disorders.

Locus Coeruleus Activation Facilitates Memory Encoding and Induces Hippocampal LTD that Depends on β-Adrenergic Receptor Activation

Spatial memory formation is enabled through synaptic information processing, in the form of persistent strengthening and weakening of synapses, within the hippocampus. It is, however, unclear how relevant spatial information is selected for encoding, in preference to less pertinent information. As the noradrenergic locus coeruleus (LC) becomes active in response to novel experiences, we hypothesized that the LC may provide the saliency signal required to promote hippocampal encoding of relevant information through changes in synaptic strength. Test pulse stimulation evoked stable basal synaptic transmission at Schaffer collateral (SC)–CA1 stratum radiatum synapses in freely behaving adult rats. Coupling of these test pulses with electrical stimulation of the LC induced long-term depression (LTD) at SC–CA1 synapses and induced a transient suppression of theta-frequency oscillations. Effects were N-methyl-D-aspartate and β-adrenergic receptor dependent. Activation of the LC also increased CA1 noradrenalin levels and facilitated the encoding of spatial memory for a single episode via a β-adrenoceptor–dependent mechanism. Our results demonstrate that the LC plays a key role in the induction of hippocampal LTD and in promoting the encoding of spatial information. This LC–hippocampal interaction may reflect a means by which salient information is distinguished for subsequent synaptic processing.

Somatosensory areas in the telencephalon of the pigeon

SummaryTwo somatosensory regions in the pigeons telencephalon were investigated electrophysiologically with recordings of field potentials as well as single- and multi-unit responses which were evoked by electrical stimulation of all four extremities or by feather movements produced with airpuffs or by hand. The outline of both areas, was studied in detail with the use of grid-like recordings of single or multi-units. One somatosensory area is located rostrally in the hyperstriatum accessorium (HA), rostral to the visual “Wulst”. A caudal area comprises the medial aspects of two different cell layers: the neostriatum intermedium (NI) and adjacent neostriatum caudale (NC) as well as the overlying hyperstriatum ventrale (HV). The two areas differ considerably in their response characteristics. Field potentials of the NI/NC-HV area were more complex than those of the HA area and their shapes and latencies varied mainly in dependence of the recording site (NI, NC, HV). Multi-unit responses showed strong excitation and short latencies in NI/NC and weak excitation and longer latencies in HV. Both responses and latencies were uniform in the HA area and latencies generally longer than in NI/NC but shorter than in HV. The HA area processes somatosensory information more specifically. Its neurons have relatively small receptive fields which seem to be arranged in a somatotopic order in such a way that rostral parts of the body are represented superficially and caudal parts in deeper layers. In contrast, the NI/NC-HV area was found to be largely multimodal, receiving also auditory and visual information. Neurons in this region have large somatic receptive fields, often including one and sometimes even both sides of the body surface. A somatotopic arrangement could not be recognized. The whole body surface was representated in both areas, but there was a dominance of wing and back receptive fields in the NI/NC-HV area and leg and neck receptive fields in the HA area.

The influence of corticofugal feedback on the temporal structure of visual responses of cat thalamic relay cells

1 Visually driven single‐unit activity was recorded in the dorsal lateral geniculate nucleus (dLGN) of the anaesthetized cat while inactivating or stimulating the corticofugal feedback from area 17/18 by means of cortical cooling or application of GABA (inactivation), or application of glutamate or quisqualate (Glu, Quis; stimulation) to layer VI. 2 Manipulations of the corticofugal feedback primarily affected the multimodal interspike interval pattern previously reported to be present in the tonic component of visual responses elicited by spot‐like stimuli. 3 Sixty‐three per cent of all neurons could be influenced, and temporally localized interspike interval distributions were measured which commonly consisted of one fundamentalinterval peak (leftmost peak) and integer multiples thereof (higher orderpeaks). During blockade of the corticofugal feedback, interspike intervals were redistributed into the higher order peaks in about 70 % of the cases, accompanied by a reduced mean firing rate. During stimulation the reverse effect occurred in 69 % of cases. 4 Increased synchronization of the EEG (increased power in the δ‐wave range, 1‐4 Hz) had an effect similar to cortex inactivation. The specificity of corticofugal effects was verified by consideration of these EEG effects and by dLGN double recordings with one dLGN cell topographically matched with the cortical inactivation/activation site and the second cell outside this area. Clear effects due to manipulation of the corticofugal feedback were found only for the matched dLGN site. 5 In addition we observed that the peaks of the interval distributions were narrower during active corticofugal feedback, such that the temporal dispersion of the signal transmission to the cortex was reduced. 6 The mechanisms underlying this effect were further analysed in a biophysically realistic model demonstrating that the timing of the spikes in the dLGN is improved as soon as the cortical feedback is active. The high degree of convergence/divergence between neurons along the closed feedback loop thereby leads to a temporal averaging effect which reduces the interval dispersion and also introduces synchronization between dLGN cells. 7 Such a mechanism may thus counteract the deterioration of spike timing accuracy which would otherwise occur as a consequence of synaptic noise and other uncorrelated sources of activity at a given neuron.

Inverse correlation of firing patterns of single topographically matched perigeniculate neurons and cat dorsal lateral geniculate relay cells

Action potentials of single perigeniculate (PGN) cells and relay cells of the dorsal lateral geniculate nucleus (dLGN) with topographically matched or at least partially overlapping receptive fields (RF) were simultaneously recorded in the anesthetized and paralyzed cat during visual stimulation with moving gratings or flashing light spots of different size. In many cases, PGN cells showed an activity pattern which appeared like a mirror image of distinct periods of dLGN activity. Flashing spots evoked transient volleys of activity in PGN cells which increased in strength and shortened in latency with increasing size of the stimulus. These responses were temporally matched with inhibitory phases in the early part of visual responses in the dLGN. The spatio-temporal properties of the RFs were established by reverse correlation of the spike activity with the spatially random presentation of bright and dark spots within an array of 20 x 20 positions. Anticorrelated firing patterns of such kind could also be elicited as interocular inhibition with stimulation of the perigeniculate RF in the nondominant eye. Inversely correlated changes in spontaneous and visually induced activity were also visible during spontaneous changes in EEG pattern. With increasing synchronization of the EEG (predominance of delta-waves) the strength of geniculate visual responses declined while maintained perigeniculate activity increased. A weakened interocular and monocular inhibition of dLGN relay cells during visual stimulation of PGN RFs could be achieved with local reversible inactivation of PGN areas topographically matched with the dLGN recording sites. The results indicate that the PGN contributes to the state-dependent control of retino-geniculate transmission and to the monocular and interocular inhibitory processes that shape the visual responses in the dLGN.

Effects of repetitive TMS on visually evoked potentials and EEG in the anaesthetized cat: dependence on stimulus frequency and train duration

Repetitive transcranial magnetic stimulation (rTMS) has been shown to alter cortical excitability that lasts beyond the duration of rTMS application itself. High‐frequency rTMS leads primarily to facilitation, whereas low‐frequency rTMS leads to inhibition of the treated cortex. However, the contribution of rTMS train duration is less clear. In this study, we investigated the effects of nine different rTMS protocols, including low and high frequencies, as well as short and long applications (1, 3 and 10 Hz applied for 1, 5 and 20 min), on visual cortex excitability in anaesthetized and paralysed cats by means of visual evoked potential (VEP) and electroencephalography (EEG) recordings. Our results show that 10 Hz rTMS applied for 1 and 5 min significantly enhanced early VEP amplitudes, while 1 and 3 Hz rTMS applied for 5 and 20 min significantly reduced them. No significant changes were found after 1 and 3 Hz rTMS applied for only 1 min, and 10 Hz rTMS applied for 20 min. EEG activity was only transiently (<20 s) affected, with increased delta activity after 1 and 3 Hz rTMS applied for 1 or 5 min. These findings indicate that the effects of rTMS on cortical excitability depend on the combination of stimulus frequency and duration (or total number of stimuli): short high‐frequency trains seem to be more effective than longer trains, and low‐frequency rTMS requires longer applications. Changes in the spectral composition of the EEG were not correlated to changes in VEP size.