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An alternative enhancement strategy directly targets the NMDA receptor. Memantine acts to enhance memory, in a somewhat contradictory fashion, by weakly antagonizing the NMDA receptor Parsons et al. This seems to have beneficial effects on cognition in Alzheimer's disease Lipton, NMDA-antagonism by memantine is thought to exert a nootropic effect in the long term as a result of protection from glutamate-induced excitotoxicity.

It is important to note that memantine does not enhance memory through a direct modulation of LTP itself, although it does rescue deficits in LTP induced by excitotoxicity Frankiewicz and Parsons, Another major strand of commercial and clinical investigation into nootropics has focused on the cAMP-dependent signalling pathway. Rolipram has been considered a potential candidate for clinical use.

Investigations into LTP in humans are obviously limited. A rare opportunity for experiments comparable with those conducted in animal models has been provided by excision of hippocampal tissue from individuals undergoing surgery as a treatment for temporal lobe epilepsy see Fig. Careful treatment of this tissue after removal from the brain has enabled investigators to test some of the molecular features of LTP in the temporal cortex Chen et al.

Substantial LTP can be induced in acute slices prepared from excised hippocampal tissue by brief tetanic stimulation of perforant path fibres. Potentiation of synaptic responses can be sustained for at least 2 h. Application of APS during the tetanus prevents the induction of LTP, demonstrating a requirement for the NMDA receptor, and sustained potentiation of synaptic responses results from bath application of forskolin, suggesting the involvement of the cAMP-dependent signalling pathway in LTP in humans.

Induction of long-term potentiation LTP in the human hippocampus. A Diagram of a hippocampal slice prepared from excised human temporal lobe. Granule and pyramidal cell fields are shaded in pink. The schematic shows the excitatory 'tri-synaptic loop comprising i perforant path PP fibres originating in the entorhinal cortex EC terminating on granule cells in the dentate gyrus DG , ii granule cells in turn projecting, via their axons, the mossy fibres, to the CA3 subfield of the hippocampus. Here the mossy fibres terminate on proximal apical dendrites of pyramidal cells. The latter in turn, project via the Schaffer collaterals to subfield CA1, where they terminate upon pyramidal neurons, the axons of which project to the subiculum Sub.

A recording electrode is shown in the dendritic field of granule cells to monitor field potentials evoked by two electrodes placed on either side to activate non-overlapping populations of PP axons. Evoked synaptic field potentials are shown in panel B. Responses prior to the delivery of a high-frequency train through one of the two stimulating electrodes are shown in black. Responses after the tetanus are shown in red. The other stimulating electrode activates a non-tetanised control pathway. Low frequency stimuli are delivered to both pathways throughout the experiment. A plot of the slope of the population EPSP against time shows a large and maintained increase in synaptic efficacy in the tetanised pathway but not in the control pathway following delivery of the high frequency train arrow C.

Adapted, with permission, from Beck et al. Patients contributing tissue to these studies fall into two groups: those with an epileptic focus in the hippocampus and those with a focus elsewhere in the temporal lobe. LTP can be readily induced in hippocampal tissue taken from patients with extra-hippocampal epileptic foci.

The degree of LTP induced by tetanic stimulation in tissue taken from patients with hippocampal epileptic foci, however, is far more modest, and potentiation cannot be induced using forskolin.

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A possible reason for these observations is that synapses in epileptic tissue have become potentiated through epileptic activity, and are near saturation. A separate study found that expression of CaMKII is elevated in dentate granule cells of patients with hippocampal epileptic foci, perhaps reflecting a compensatory alteration of CaMKII signalling Lie et al. Finally, patients with hippocampal foci perform worse on the Rey verbal memory task than individuals with neo-cortical temporal lobe epileptic foci Helmstaedter et al.

This series of results from human subjects comprises a set of correlations between synaptic LTP, declarative memory, the NMDA receptor and intracellular signalling mechanisms that have previously been identified in animal models. Technical advances have presented the possibility of delivering tetanic stimulation to awake human subjects. This can be achieved using repetitive transcranial magnetic stimulation rTMS , in which the cerebral cortex of an awake human subject can be stimulated non-invasively with a remote hand-held apparatus.

Interventional paired associative stimulation IPAS , which pairs TMS with electrical stimulation of peripheral nerves that provide input to the same cortical region, can be used in a similar manner. The risks of inducing seizure or long-lasting pathologies have had to be carefully evaluated before proceeding with experiments using remote stimulation with the high frequencies necessary for inducing LTP Wassermann et al.

Experiments using these technologies have not focused on the medial temporal lobe for two major reasons. First, the hippocampus and surrounding structures lie deeper than 2 cm below the surface of the skull in humans, the current limiting distance for application of TMS Bohning et al. For these reasons many TMS studies have been conducted in the motor cortex where remote stimulation can be used to elicit limb movements Pridmore et al. This positive control allows investigators to establish a motor threshold, which varies greatly from individual to individual, and set experimental stimulation intensity accordingly.

In addition, monitoring motor output allows for the observation of long-term behavioural consequences of higher-frequency remote stimulation. TMS stimulation of motor cortex in humans using frequencies of 1—20 Hz produces effects on motor-evoked potentials that vary from individual to individual. Generally, 1 Hz stimulation reduces neural activity and anything over 5 Hz increases activity and motor output. In both cases the effects of such stimulation appear to be transient, lasting around half an hour at most Hallett, Interestingly, application of this low-frequency TMS to area M1 in the motor cortex can be used to block consolidation of motor skill acquisition in normal human subjects without interfering with motor performance itself Muellbacher et al.

Although changes in evoked potentials persist after the higher-frequency 5 Hz trains of stimuli, the effect is not consistent and never lasts long enough to be comparable with LTP Maeda et al. Higher-frequency tetani 50 Hz have now been delivered and shown to be safe in normal individuals, provided the intensity of the stimulation is reduced to below motor threshold, although even this mode of stimulation does not produce changes that persist for longer than hundreds of milliseconds Huang and Rothwell, LTP is often induced in animals using repeated trains of high-frequency stimulation spaced at a frequency that mimics a spontaneous Hz neural rhythm, the theta wave.

Tetani of this sort via TMS can induce long-lasting changes in motor cortical output Huang et al. Again the frequency of stimulation never exceeds 50 Hz in this sort of experiment [animal investigators may use frequencies as high as Hz Davis et al. This finding strongly suggests that remote stimulation can be used to induce a long-lasting change in motor cortical output. It has yet to be demonstrated, however, that the site of such change is the synapse. As described above, an alternative means of inducing LTP that does not require the application of a high-frequency tetanus, is to pair pre- and post-synaptic action potentials Wigstrom et al.

Pairing of this sort can potentially be modelled in humans by combining low-frequency TMS to the cortex whilst simultaneously stimulating a peripheral nerve, an approach known as IPAS see Fig. For example, peripheral stimulation of the right median nerve can be followed by TMS directed at the hand representation area in contralateral primary motor cortex M1 , at a latency determined by the time-lag in evoking an M1 cortical potential via activation of somatosensory cortex Stefan et al. Motor-evoked potentials can again be used as an index of the resultant increase in motor cortical output, here in the abductor pollicis brevis muscle in the thumb.

One benefit of using this approach compared with high-frequency TMS is that any risk of seizure is greatly reduced. Another is that it is more physiologically realistic and enables the testing of one of the key requirements for LTP—coincident pre- and post-synaptic activity. While coincident pre- and post-synaptic stimulation in the cortex, using peripheral stimulation preceding TMS stimulation, results in an increase in cortical excitability lasting for at least an hour Stefan et al.

Both of these effects can be blocked by the NMDA receptor antagonist dextromethorphan. Moreover, the plasticity is limited to only those cells receiving stimulation in the cortex due to both peripheral stimulation and direct TMS, as demonstrated by the fact that there is no potentiation of motor-evoked responses in muscles controlled by neighbouring regions of motor cortex, such as the biceps brachii, which receive TMS stimulation but not peripherally induced stimulation. This experiment establishes that the potentiating effect is restricted to cells receiving paired input.

Recent experiments reveal that motor learning prior to IPAS stimulation can prevent induction of the LTP-like plasticity in motor cortex for a period of 6 h Stefan et al. Again, this finding suggests that the early motor learning may have saturated plasticity, thereby occluding further change.

At the same time, the induction of LTD-like plasticity during this same period is facilitated Ziemann et al. Interventional paired associative stimulation IPAS. Transcranial magnetic stimulation TMS is delivered to the hand representation area in region M1 of the motor cortex with single test pulses at an intensity set to elicit a motor evoked potential MEP in the abductor pollicis brevis APB muscle of the thumb.

Electrical stimuli to the median nerve are paired with TMS e. The potentiation of the MEP can last for at least an hour. MEPs represent averages of 20 samples. Adapted, with permission, from Stefan et al. An alternative to TMS has recently been used to induce long-lasting changes in neuronal excitability in human subjects, this time in the auditory Clapp et al. ERPs can be recorded in either area using scalp electrodes to monitor responses to auditory or visual stimuli. In these experiments, long-lasting enhancement of the amplitude of a component of either auditory-evoked or visual-evoked responses is achieved using a 13 Hz auditory tetanus, comprising a sequence of tone pips, or a photic tetanus generated on a computer screen, which comprises a series of chequerboard stimuli delivered at a frequency of 9 Hz.

Either of these tetani is sufficient to increase the amplitude of a component of ERP in the respective area of cortex for at least 50 min afterwards. Moreover, in the latter case, delivery of lower-frequency visual stimuli 1 Hz reduces the amplitude back to baseline levels, suggesting a depotentiation-like process. The authors of these studies argue that the selective alteration of a single component of the ERP, which consists of electrical fields generated by a large number of neurons, constitutes a form of synaptic plasticity.

This interpretation cannot be validated without more refined analysis, which, with the limits of current technology, is not yet possible. Nonetheless, it is a fascinating finding that a sensory tetanus alone can be used to induce long-lasting effects on neuronal responses in cerebral cortex. The finding complements animal studies in which LTP is induced at synapses made by fibres from projection neurons in the lateral geniculate nucleus on layer IV cells in the visual cortex pathway of rats Heynen and Bear, Here LTP is induced by tetanic electrical stimulation, but subsequent to the tetanus, responses in primary visual cortex evoked by visual stimuli, such as light flashes and patterned gratings, are enhanced.

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Regardless of the means of stimulation—whether TMS, IPAS, or photic or acoustic tetani—the end result is a long-lasting increase in cortical responsiveness. As yet, however, investigators have not been able to establish the exact nature of the underlying neural plasticity. Possibilities include changes in synaptic efficacy or in the threshold for action potential generation in the excitatory output cells of the cortex, or changes of similar sorts in intrinsic inhibitory networks.

It is possible to observe alteration of activity in the neocortex using remote recording technology with electroencephalogram scalp electrodes Clapp et al. EPSP-spike E—S potentiation, another form of neural plasticity in which the probability of an action potential being generated by a given synaptic input is increased, may well play a significant role in learning and memory Giese et al. However, E—S potentiation is unlikely to provide the same capacity for information storage as potentiation of chemical transmission at individual synapses, because changes in the mechanism of action potential generation should, in theory, have an equivalent effect on many inputs to the same cell.

Curiously, there is some evidence for a degree of input specificity in E—S plasticity Douadal et al. However, it is likely that the specificity is limited to small populations of synapses rather than individual synapses. At this point it is important to stress that the only direct evidence for synaptic plasticity in the human CNS comes from the experiments described earlier on excised human tissue Chen et al. All those studies that we have described so far using remote means to induce changes in neuronal excitability and functional output of the human CNS in awake subjects are consistent with the induction of LTP or LTD at synapses.

However, in order to demonstrate in these cases that change occurs in the efficacy of synaptic transmission rather than in the excitability of the cell, or in the balance of excitation and inhibition in the network in which the cell is embedded, it will be necessary to conduct experiments in which synaptic responses are monitored to activation of two clearly defined, and separately stimulated, input pathways. If change is synaptic it should be possible to potentiate or depress responses to one pathway without interfering with the other see Fig.

Current approaches to non-invasive recording and stimulation have not yet allowed such observations to be made. Regardless of whether it is synaptic efficacy that is altered for long periods, or some other long-lasting form of neural plasticity, the net effect of the stimulation protocols described above is an increase in output from the neocortex. Repetitive stimulation of the brain can exert long-lasting functional effects, as demonstrated by the increased muscle activity in the hand in response to TMS directed at primary motor cortex.

Treatment could potentially be provided for neurological disorders that arise from a reduction in the output of particular regions of the brain, as in Parkinson's disease and depression, using remote stimulation to induce long-lasting increases in excitatory drive. Currently available therapies using electrical stimulation rely upon invasive surgery. A non-invasive method of achieving the same end would obviously be preferable.

Electroconvulsive therapy ECT has long been used to treat depression in cases in which other treatments fail Potter and Rudorfer, This is an extreme measure that, although effective in some cases, can also result in memory loss and other cognitive deficits Frasca et al. A number of studies have shown significant anti-depressant effects of rTMS between 1 and 20 Hz , delivered to the prefrontal cortex, in patients with medication-resistant depression, as assessed using objective scales George et al.

It has been suggested that the use of theta burst rTMS, as recently demonstrated by Huang et al. A major concern with this method is the possibility that mania may result from increased activity in the same prefrontal areas targeted with rTMS Kaptsan et al. Nonetheless, treatment of depression with rTMS is a promising avenue of clinical research. The use of rTMS to treat Parkinson's disease may be of less obvious therapeutic value. It is well known that the primary site of degeneration in this disease is a deep-lying midbrain structure—the substantia nigra.

This is not accessible to remote stimulation with TMS. However, it is possible that some of the secondary effects of reduced nigral output, such as disrupted motor cortical activity, may be open to manipulation with non-invasive stimulation over the scalp. Basal ganglia dysfunction resulting in reduced nigral output results in characteristic synchronized activity in the motor cortex that is believed to contribute to akinesia and limb rigidity Goldberg et al.

It has been shown that high-frequency stimulation targeted at the M1 area of the motor cortex can induce recovery from Parkinson's-like motor deficits in baboons treated with the toxin 1-methylphenyl-1,2,3,6-tetrahydropyridine MPTP. MPTP selectively kills dopaminergic neurons in the substantia nigra, thereby affecting basal ganglia function and initiating the parkinsonian symptoms of akinesia, bradykinesia, tremor and rigidity.

Curiously, given the fact that motor cortical activity is not reduced by MPTP-induced pathology, but is instead simply highly synchronized, delivery of high-frequency Hz stimulation of the motor cortex, which presumably boosts motor cortical activity if it induces LTP, results in a significant long-lasting functional recovery from symptoms of akinesia and bradykinesia in MPTP-treated baboons Drouot et al.

The rationale behind this approach is somewhat counter-intuitive but the technique seems to produce results. Recently developed invasive therapies are beginning to yield some success in the treatment of Parkinson's disease Houeto et al. In order to mimic the output of the substantia nigra, electrodes are implanted into the sub-thalamic nucleus or internal segment of the globus pallidus, basal ganglia components that lie downstream of the substantia nigra. However, this is a very difficult surgical procedure and involves significant risk.

Non-invasive therapy may be preferable, even if it requires multiple treatments, so further research into the effects and side-effects of non-invasive motor cortex stimulation in Parkinson's models may yet lead to significant amelioration of symptoms. A final potential application for TMS is in the treatment of intractable epilepsy, a probable contributory factor to which is increased efficacy of glutamatergic synaptic transmission or reduced inhibition at a neuronal population level. It is possible that neuronal hyperexcitability in epilepsy could be reduced by induction of LTD.

LTD may either de-potentiate over-potentiated synapses or compensate for other causes of hyperexcitability. Application of low-frequency rTMS 0. Further development of this approach seems warranted, given the demonstrations that it can be used to induce an LTD-like phenomenon in the neocortex Chen et al. LTD induction may also have therapeutic value in the treatment of chronic neuropathic pain. Hyperalgesia of this sort can be modelled in rodents by injecting formalin subcutaneously into a paw.

Alterations of central circuitry within the spinal cord occur that, in turn, mediate a long-lasting hypersensitivity to cutaneous stimulation around the conditioning site Woolf et al. This model has enabled the identification of cell types and signalling pathways involved in long-lasting central sensitization reviewed in Han, , and has also suggested the involvement of synaptic LTP in the induction of hyperalgesia reviewed in Ji et al.

Synapses between primary afferent peptidergic nociceptive fibres, which release substance P as a neurotransmitter, and projection neurons from lamina I of the dorsal horn of the spinal cord expressing the neurokinin 1 NK1 receptor, which binds substance P, can display LTP in response to high-frequency stimulation. Neighbouring cells that receive nociceptive input but do not express the NK1 receptor do not exhibit LTP. If chronic neuropathic pain is mediated by LTP at a limited population of synapses then a logical approach to treatment would be to attempt to induce LTD at these same synapses.

A recent study has used transcutaneous electrical nerve stimulation TENS to deliver high- and low-frequency tetani in human subjects in order to induce long-term hyper- and hypoalgesia, respectively, in response to mechanical stimulation of surrounding skin Klein et al. Here ratings of pain levels by the subjects serve as an index of the degree of sensitization or analgesia. Although pain was reported to increase acutely during both high- and low-frequency stimulation, reported pain levels were persistently increased after high-frequency stimulation and decreased after low-frequency stimulation.

Thirty years of research into LTP has yielded a huge amount of data on the properties of longevity, input specificity and associativity, on the molecular mechanisms that support both short-lasting and persistent LTP, and on the correlation between LTP and learning and memory reviewed in Bliss et al. We are not yet in a position to conclude definitively that LTP provides a mechanism for the neural basis of learning and memory but it is certainly a compelling physiological model of these processes.

Animal studies during the past three decades have covered a wide range of preparations, from dissociated cell cultures to awake, freely moving animals, but only recently has progress been made in the study of LTP in humans. Synaptic LTP can be induced in hippocampal tissue excised from human patients, and this plasticity, unsurprisingly, shares molecular mechanisms with animal models.

Moreover, deficits in LTP are correlated with deficits in hippocampus-dependent memory in humans. Progress in remote stimulation technology is now making it possible to consider treatments based on the induction of long-lasting changes in cortical output using stimulation protocols similar to those that have been used to induce synaptic plasticity in animals. Similar treatments may also be beneficial for other neurological disorders such as Parkinson's disease and epilepsy.

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Long-term potentiation. Molecular mechanisms. LTP and memory in rodents. Memory mechanisms in humans. LTP in humans. Non-invasive stimulation in awake humans. Transcranial magnetic stimulation. Interventional paired associative stimulation. Auditory and photic stimulation. Neural plasticity and therapy. Parkinson's disease. Plasticity in the human central nervous system S.

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Cite Citation. Permissions Icon Permissions. Abstract Long-term potentiation LTP is a well-characterized form of synaptic plasticity that fulfils many of the criteria for a neural correlate of memory. View large Download slide. Search ADS. Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus. A molecular switch for the consolidation of long-term memory: cAMP-inducible gene expression. Possible mechanisms for long-lasting potentiation of synaptic transmission in hippocampal slices from guinea-pigs.

Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Medial temporal lobe activation during semantic language processing: fMRI findings in healthy left- and right-handers.

Plasticity of the human brain | Max-Planck-Gesellschaft

Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path.

Eliciting brain plasticity to keep the body moving - Science Nation

Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path. Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein.

Long-term modifications of synaptic efficacy in the human inferior and middle temporal cortex. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation.

Brain Plasticity: Re-shaping the Mind

The basic structure of the brain is established before birth by your genes. But its continued development relies heavily on a process called developmental plasticity, where developmental processes change neurons and synaptic connections. In the immature brain this includes making or losing synapses, the migration of neurons through the developing brain or by the rerouting and sprouting of neurons. There are very few places in the mature brain where new neurons are formed.

The exceptions are the dentate gyrus of the hippocampus an area involved in memory and emotions and the sub-ventricular zone of the lateral ventricle , where new neurons are generated and then migrate through to the olfactory bulb an area involved in processing the sense of smell. Although the formation of new neurons in this way is not considered to be an example of neuroplasticity it might contribute to the way the brain recovers from damage.

As the brain grows, individual neurons mature, first by sending out multiple branches axons, which transmit information from the neuron, and dendrites, which receive information and then by increasing the number of synaptic contacts with specific connections. At birth, each infant neuron in the cerebral cortex has about 2, synapses. By two or three-years-old, the number of synapses per neuron increases to about 15, as the infant explores its world and learns new skills — a process called synaptogenesis.

But by adulthood the number of synapses halves , so-called synaptic pruning. Whether the brain retains the ability to increase synaptogenesis is debatable, but it could explain why aggressive treatment after a stroke can appear to reverse the damage caused by the lack of blood supply to an area of the brain by reinforcing the function of undamaged connections. We continue to have the ability to learn new activities, skills or languages even into old age.

This retained ability requires the brain to have a mechanism available to remember so that knowledge is retained over time for future recall. This is another example of neuroplasticity and is most likely to involve structural and biochemical changes at the level of the synapse. Reinforcement or repetitive activities will eventually lead the adult brain to remember the new activity. By the same mechanism, the enriched and stimulating environment offered to the damaged brain will eventually lead to recovery.

The answer is that it depends on your age younger brains have a better chance of recovery , the size of the area damaged and, more importantly, the treatments offered during rehabilitation. The polar oceans and global climate — Milton Keynes, Buckinghamshire. Aesthetics, politics and pleasure: How literature transforms us — York, York. Edition: Available editions United Kingdom. Duncan Banks , The Open University. The malleable brain.