Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning

Several lines of evidence suggest that schizophrenia (SCZ) is associated with disrupted plasticity in the cortex. However, there is little direct neurophysiological evidence of aberrant long-term potentiation (LTP)-like plasticity in SCZ and little human evidence to establish a link between LTP to learning and memory. LTP was evaluated using a neurophysiological paradigm referred to as paired associative stimulation (PAS). PAS involves pairing of median nerve electric stimulation with transcranial magnetic stimulation (TMS) over the contralateral motor cortex (for abductor pollicis brevis muscle activation) delivered at 25-ms interstimulus interval. This pairing was delivered at a frequency of 0.1 Hz for 30 min. LTP was reflected by the change in motor evoked potentials (MEPs) before and after PAS. In addition, motor skill learning was assessed using the rotary pursuit task. Compared with healthy subjects, patients with SCZ demonstrated significant MEP facilitation deficits following PAS and impaired rotary-pursuit motor learning. Across all subjects there was a significant association between LTP and motor skill learning. These data provide evidence for disrupted LTP in SCZ, whereas the association between LTP with motor skill learning suggests that the deficits in learning and memory in SCZ may be mediated through disordered LTP.     

Deficient homeostatic regulation of practice-dependent plasticity in writer's cramp

Homeostatic metaplasticity is important to maintain overall synaptic weight in neuronal networks. Previous work suggested that homeostatic metaplasticity in motor cortex is impaired in writer's cramp, the most common form of task-specific focal dystonia, when explored by the interactions between 2 successive plasticity inducing transcranial brain stimulation protocols (Quartarone Rizzo V, Bagnato S, Morgante F, Sant'angelo A, Romano M, Crupi D, Girlanda P, Rothwell JC, Siebner HR. 2005. Homeostatic-like plasticity of the primary motor hand area is impaired in focal hand dystonia. Brain. 128:1943-1950.). To which extent deficient homeostatic metaplasticity applies also to the behavioral level of practice-dependent plasticity is unknown. Here, we examined the interactions of 3 paired associative transcranial magnetic stimulation protocols (motor cortical excitability-enhancing paired associative stimulation (PAS)(25ms), excitability-depressing PAS(10ms), and control PAS(100ms)) with subsequent practice-dependent plasticity. Ten patients with writer's cramp and 10 healthy controls practiced rapid thumb abductions for 30 min. Practice-dependent plasticity was quantified by the increase in peak acceleration of the trained movement. The healthy controls but not the writer's cramp patients showed homeostatic suppression of practice-dependent plasticity after PAS(25ms) when compared with practice-dependent plasticity after PAS(10ms) and PAS(100ms). The lack of the PAS(25ms)-induced suppression of practice-dependent plasticity in writer's cramp correlated with clinical severity of the focal hand dystonia. Findings support the notion that deficient homeostatic metaplasticity of practice-dependent plasticity plays a significant role in the pathophysiology of writer's cramp.     

Altered bidirectional plasticity and reduced implicit motor learning in concussed athletes

Persistent motor/cognitive alterations and increased prevalence of Alzheimer's disease are known consequences of recurrent sports concussions, the most prevalent cause of mild traumatic brain injury (TBI) among youth. Animal models of TBI demonstrated that impaired learning was related to persistent synaptic plasticity suppression in the form of long-term potentiation (LTP) and depression (LTD). In humans, single and repeated concussive injuries lead to lifelong and cumulative enhancements of gamma-aminobutyric acid (GABA)-mediated inhibition, which is known to suppress LTP/LTD plasticity. To test the hypothesis that increased GABAergic inhibition after repeated concussions suppresses LTP/LTD and contributes to learning impairments, we used a paired associative stimulation (PAS) protocol to induce LTP/LTD-like effects in primary motor cortex (M1) jointly with an implicit motor learning task (serial reaction time task, SRTT). Our results indicate that repeated concussions induced persistent elevations of GABA(B)-mediated intracortical inhibition in M1, which was associated with suppressed PAS-induced LTP/LTD-like synaptic plasticity. This synaptic plasticity suppression was related to reduced implicit motor learning on the SRTT task relative to normal LTP/LTD-like synaptic plasticity in unconcussed teammates. These findings identify GABA neurotransmission alterations after repeated concussions and suggest that impaired learning after multiple concussions could at least partly be related to compromised GABA-dependent LTP/LTD synaptic plasticity.     

Boosting focally-induced brain plasticity by dopamine

Dopamine (DA) simultaneously produces both excitation and inhibition in the human cortex. In order to shed light on the functional significance of these seemingly opposing effects, we administered the DA precursor levodopa (L-dopa) to healthy subjects in conjunction with 2 neuroplasticity-inducing motor cortex stimulation protocols. Transcranial direct current stimulation (tDCS) induces cortical excitability enhancement by anodal and depression by cathodal brain polarization, which is not restricted to specific subgroups of synapses. In contrast, paired associative stimulation (PAS) induces focal excitability enhancements of somatosensory and motor cortical neuronal synaptic connections. Here, we show that administering L-dopa turns the unspecific excitability enhancement caused by anodal tDCS into inhibition and prolongs the cathodal tDCS-induced excitability diminution. Conversely, it stabilizes the PAS-induced synapse-specific excitability increase. Most importantly, it prolongs all of these aftereffects by a factor of about 20. Hereby, DA focuses synapse-specific excitability-enhancing neuroplasticity in human cortical networks.     

Paired associative stimulation of left and right human motor cortex shapes interhemispheric motor inhibition based on a Hebbian mechanism

This study was designed to examine whether corticocortical paired associative stimulation (cc-PAS) can modulate interhemispheric inhibition (IHI) in the human brain. Twelve healthy right-handed volunteers received 90 paired transcranial stimuli to the right and left primary motor hand area (M1(HAND)) at an interstimulus interval (ISI) of 8 ms. Left-to-right cc-PAS (first pulse given to left M1(HAND)) attenuated left-to-right IHI for one hour after cc-PAS. Left-to-right cc-PAS also increased corticospinal excitability in the conditioned right M1(HAND). These effects were not seen in an asymptomatic individual with callosal agenesis. Additional experiments showed no changes in left-to-right IHI or corticospinal excitability when left-to-right cc-PAS was given at an ISI of 1 ms or at multiple ISIs in random order. At the behavioral level, left-to-right cc-PAS speeded responses with the left but not right index finger during a simple reaction time task. Right-to-left cc-PAS (first pulse given to right M1(HAND)) reduced right-to-left IHI without increasing corticospinal excitability in left M1(HAND). These results provide a proof of principle that cc-PAS can induce associative plasticity in connections between the targeted cortical areas. The efficacy of cc-PAS to induce lasting changes in excitability depends on the exact timing of the stimulus pairs suggesting an underlying Hebbian mechanism.     

Activity-dependent modulation of synaptic transmission in the intact human motor cortex revealed with transcranial magnetic stimulation

Activity-dependent modulation of cortical synaptic transmission is a fundamental mechanism involved in learning and memory storage. This modulation has been widely studied in in vitro brain slices and in vivo animal models. More recently, transcranial magnetic stimulation has allowed detection of activity-dependent excitability modulation occurring in the intact human primary motor cortex (MI) after execution of different kinds of motor tasks. Both increased and decreased MI excitability have been described after exercise. While increased MI excitability is generally considered direct expression of cortical synaptic plasticity, a controversy still exists as to whether decreased MI excitability reflects fatigue of central nervous system (CNS) structures or cortical neuronal reorganization taking place after exercise. Here, we extend previous findings in order to provide further support for the latter hypothesis. Abduction- adduction movements of the thumb performed for 1 min at 2 Hz frequency rate produce a 55% decrease in MI excitability of mean 30 min duration. Similar decrements in amplitude and duration of motor evoked potentials (MEPs) are not reached if the same task is performed once again during the maximal inhibition phase (10 min post-exercise) produced by a previous activation. Moreover, the same task performed at a lower (1 Hz) frequency rate produces no significant MEP changes but can transiently reverse activity-dependent depression obtained after previous 2 Hz movements. Repeated execution of the same task (2 Hz), each being performed after recovery from a previously induced MEP depression, ceases to produce an MEP decrement, suggesting adaptation in MI excitability modulation. This adaptation is long lasting and task-specific, since a different motor task (1 min circular movement of the thumb) restores activity-dependent modulation. Overall, these findings suggest that the dynamic modulation of MEPs occurring after execution of different kinds of simple motor skills reflects some form of activity-dependent, plastic neuronal reorganization instead of CNS fatigue. Possible anatomo-functional mechanisms involved in this activity-dependent modulation of MI excitability are discussed.     

Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex

Although sensory and motor systems support different functions, both systems exhibit experience-dependent cortical plasticity under similar conditions. If mechanisms regulating cortical plasticity are common to sensory and motor cortices, then methods generating plasticity in sensory cortex should be effective in motor cortex. Repeatedly pairing a tone with a brief period of vagus nerve stimulation (VNS) increases the proportion of primary auditory cortex responding to the paired tone (Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake J, Sudanagunta SP, Borland MS, Kilgard MP. 2011. Reversing pathological neural activity using targeted plasticity. Nature. 470:101-104). In this study, we predicted that repeatedly pairing VNS with a specific movement would result in an increased representation of that movement in primary motor cortex. To test this hypothesis, we paired VNS with movements of the distal or proximal forelimb in 2 groups of rats. After 5 days of VNS movement pairing, intracranial microstimulation was used to quantify the organization of primary motor cortex. Larger cortical areas were associated with movements paired with VNS. Rats receiving identical motor training without VNS pairing did not exhibit motor cortex map plasticity. These results suggest that pairing VNS with specific events may act as a general method for increasing cortical representations of those events. VNS movement pairing could provide a new approach for treating disorders associated with abnormal movement representations.     

Monocular visual deprivation suppresses excitability in adult human visual cortex

The adult visual cortex maintains a substantial potential for plasticity in response to a change in visual input. For instance, transcranial magnetic stimulation (TMS) studies have shown that binocular deprivation (BD) increases the cortical excitability for inducing phosphenes with TMS. Here, we employed TMS to trace plastic changes in adult visual cortex before, during, and after 48 h of monocular deprivation (MD) of the right dominant eye. In healthy adult volunteers, MD-induced changes in visual cortex excitability were probed with paired-pulse TMS applied to the left and right occipital cortex. Stimulus-response curves were constructed by recording the intensity of the reported phosphenes evoked in the contralateral visual field at range of TMS intensities. Phosphene measurements revealed that MD produced a rapid and robust decrease in cortical excitability relative to a control condition without MD. The cortical excitability returned to preinterventional baseline levels within 3 h after the end of MD. The results show that in contrast to the excitability increase in response to BD, MD acutely triggers a reversible decrease in visual cortical excitability. This shows that the pattern of visual deprivation has a substantial impact on experience-dependent plasticity of the human visual cortex.     

Modification of practice-dependent plasticity in human motor cortex by neuromodulators

Practice-dependent plasticity underlies motor learning in everyday life and motor relearning after lesions of the nervous system. Previous studies showed that practice-dependent plasticity is modifiable by neuromodulating transmitters such as norepinephrine (NE), dopamine (DA) or acetylcholine (ACh). Here we explored, for the first time comprehensively and systematically, the modifying effects of an agonist versus antagonist in each of these neuromodulating transmitter systems on practice-dependent plasticity in healthy subjects in a placebo-controlled, randomized, double-blind crossover design. We found that the agonists in all three neuromodulating transmitter systems (NE: methylphenidate; DA: cabergoline; ACh: tacrine) enhanced practice-dependent plasticity, whereas the antagonists decreased it (NE: prazosin; DA: haloperidol; ACh: biperiden). Enhancement of plasticity under methylphenidate and tacrine was associated with an increase in corticomotoneuronal excitability of the prime mover of the practice, as measured by the motor evoked potential amplitude, but with a decrease under cabergoline. Our findings demonstrate that agonists and antagonists in various neuromodulating transmitter systems produce significant and oppositely directed modifications of practice-dependent plasticity in human motor cortex. Enhancement of plasticity occurred through different strategies that either favoured extrinsic (NE, ACh) or intrinsic (DA) modulating influence on the motor cortical output network.     

Abnormal cortical synaptic plasticity in primary motor area in progressive supranuclear palsy

No study has yet investigated whether cortical plasticity in primary motor area (M1) is abnormal in patients with progressive supranuclear palsy (PSP). We studied M1 plasticity in 15 PSP patients and 15 age-matched healthy subjects. We used intermittent theta-burst stimulation (iTBS) to investigate long-term potentiation (LTP) and continuous TBS (cTBS) to investigate long-term depression (LTD)-like cortical plasticity in M1. Ten patients underwent iTBS again 1 year later. We also investigated short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in M1 with paired-pulse transcranial magnetic stimulation, tested H reflex from upper limb flexor muscles before and after iTBS, and measured motor evoked potential (MEP) input-output (I/O) curves before and after iTBS. iTBS elicited a significantly larger MEP facilitation after iTBS in patients than in healthy subjects. Whereas in healthy subjects, cTBS inhibited MEP, in patients it significantly facilitated MEPs. In patients, SICI was reduced, whereas ICF was normal. H reflex size remained unchanged after iTBS. Patients had steeper MEP I/O slopes than healthy subjects at baseline and became even more steeper after iTBS only in patients. The iTBS-induced abnormal MEP facilitation in PSP persisted at 1-year follow-up. In conclusion, patients with PSP have abnormal M1 LTP/LTD-like plasticity. The enhanced LTP-like cortical synaptic plasticity parallels disease progression.     

Misconceptions about mirror-induced motor cortex activation

Observation of self-produced hand movements through a mirror, creating an illusion of the opposite hand moving, was recently reported to induce ipsilateral motor cortex activation, that is, motor cortex activation for the hand in rest. The reported work goes far beyond earlier work on motor cortex activation induced by action observation, by implying a complete reversal of contralateral and ipsilateral motor cortex activation under mirror view conditions. Such a reversal would represent an unprecedented degree of neural plasticity. We considered such a reversal physiologically implausible and conducted a study with an improved design. The results refute the reversal of contralateral and ipsilateral motor cortex activation under mirrored viewing conditions as methodologically unsound. The investigation confirmed, however, more subtle expressions of motor cortical activity induced by self-produced movements observed through a mirror.     

Roles of protein kinase A and protein kinase G in synaptic plasticity in the visual cortex

Monocular deprivation leads to clear physiological and anatomical changes in the visual cortex known as ocular dominance plasticity. Protein kinase A (PKA) is necessary for ocular dominance plasticity, while protein kinase G (PKG) is not. We have now tested the role of PKA and PKG in long-term potentiation (LTP) and long-term depression (LTD). We have shown that PKA inhibitors have a major effect on both LTP and LTD in the visual cortical slices, whereas a PKG inhibitor affects LTP but not LTD. The PKA activator, 8-chloroadenosine-3',5'-monophosphorothioate, Sp-isomer (Sp-8-Cl-cAMPS), by itself induces a slowly rising form of LTP, which is occluded by theta-burst stimulation (TBS)-induced LTP. These results support the point that the PKA signaling pathway is crucial for neuronal plasticity in visual cortex, and the dissociation of the role of PKA and PKG in long-term synaptic plasticity in the visual cortex suggests that LTP alone is not sufficient to support ocular dominance plasticity, or LTD plays a more fundamental role than LTP in ocular dominance plasticity.     

The effect of water maze spatial training on posterior parietal cortex transcallosal evoked field potentials in the rat

Long-term potentiation (LTP) is the principal model of synaptic plasticity often used to explain the changes that occur in the brain as a result of learning and memory. In this experiment the relationship between rat posterior parietal cortex (PPC) transcallosal evoked field potentials (TCEPs) and spatial training in the water maze was examined to determine if LTP-like changes (i.e. learning-induced LTP) in PPC TCEPs occur as a result of spatial training. Spatial training consisted of 10 trials per day for 10 consecutive days. The location of the hidden platform was changed over the course of spatial training to ensure the rats' acquisition of several different platform positions. TCEPs were taken 1 and 23 h after each training session. Upon completion of all water maze training, the animals were administered LTP-inducing trains to ensure that the recording arrangement and procedure was capable of detecting LTP. The results showed that the rats quickly acquired the water maze task and that the recording arrangement and procedure were capable of detecting LTP, even after the first session of induction. However, despite robust place learning, the TCEPs taken after water maze training did not differ from those taken before water maze training. Although the present results failed to provide any evidence for a role of neocortical LTP in learning and memory, further studies of this nature are required to determine if the present results generalize to different behavioural tasks and/or cortical areas.      

Human θ burst stimulation enhances subsequent motor learning and increases performance variability

Intermittent theta burst stimulation (iTBS) transiently increases motor cortex excitability in healthy humans by a process thought to involve synaptic long-term potentiation (LTP), and this is enhanced by nicotine. Acquisition of a ballistic motor task is likewise accompanied by increased excitability and presumed intracortical LTP. Here, we test how iTBS and nicotine influences subsequent motor learning. Ten healthy subjects participated in a double-blinded placebo-controlled trial testing the effects of iTBS and nicotine. iTBS alone increased the rate of learning but this increase was blocked by nicotine. We then investigated factors other than synaptic strengthening that may play a role. Behavioral analysis and modeling suggested that iTBS increased performance variability, which correlated with learning outcome. A control experiment confirmed the increase in motor output variability by showing that iTBS increased the dispersion of involuntary transcranial magnetic stimulation-evoked thumb movements. We suggest that in addition to the effect on synaptic plasticity, iTBS may have facilitated performance by increasing motor output variability; nicotine negated this effect on variability perhaps via increasing the signal-to-noise ratio in cerebral cortex.     

Cortical plasticity following upper extremity injury and reconstruction

Today's view of the adult central nervous system is that of an adaptive and responsive system. Plastic surgeons, because of the motor and sensory reconstructions they perform, need to have an understanding of brain plasticity following upper extremity injury, reconstruction, and rehabilitation. Functional MRI and transcranial magnetic stimulation can identify cortical plasticity in humans. For instance, these techniques have identified changes in excitability and body site representation in the motor cortex in patients following motor reconstruction and motor relearning. Therefore, cortical plasticity and its manipulation may be an important contributor to functional outcome following reconstruction. In the future, cortical plasticity may have implications for reconstruction and rehabilitation.     

Imagery-induced cortical excitability changes in stroke: a transcranial magnetic stimulation study

Focal transcranial magnetic stimulation (TMS) was employed in a population of hemiparetic stroke patients in a post-acute stage to map out the abductor digiti minimi (ADM) muscle cortical representation of the affected (AH) and unaffected (UH) hemisphere at rest, during motor imagery and during voluntary contraction. Imagery induced an enhancement of the ADM map area and volume in both hemispheres in a way which partly corrected the abnormal asymmetry between AH and UH motor output seen in rest condition. The voluntary contraction was the task provoking maximal facilitation in the UH, whereas a similar degree of facilitation was obtained during voluntary contraction and motor imagery in the AH. We argued that motor imagery could induce a pronounced motor output enhancement in the hemisphere affected by stroke. Further, we demonstrated that imagery-induced excitability changes were specific for the muscle 'prime mover' for the imagined movement, while no differences were observed with respect to the stroke lesion locations. Present findings demonstrated that motor imagery significantly enhanced the cortical excitability of the hemisphere affected by stroke in a post-acute stage. Further studies are needed to correlate these cortical excitability changes with short-term plasticity therefore prompting motor imagery as a 'cortical reservoir' in post-stroke motor rehabilitation.     

Impaired synaptic plasticity in the surround of perinatally acquired [correction of aquired] dysplasia in rat cerebral cortex

Freeze-lesion induced neocortical dysplasias in rats mimic numerous aspects of human polymicrogyria and are used as a model for the study of developmental migration disorders. Since memory tests have demonstrated learning deficits in rodents with neocortical malformations, we investigated the expression and properties of long-term potentiation (LTP) in neocortical slices from adult freeze-lesioned and control rats. Field potentials, recorded in layer II/III at a distance of 2-3 mm lateral to perinatally induced microgyri, were strongly enhanced following theta-burst stimulation in layer VI (amplitude: 174 +/- 4%) compared to controls (110 +/- 2%). In contrast, in layer IV of the freeze-lesioned cortex LTP could not reliably be induced. Histochemical analysis, performed to elucidate the cellular basis of the impaired plasticity, revealed diminished amounts of the GABAA-receptor subunit gamma2 in the paramicrogyral zone, likely representing a diminished GABA-ergic filter, which is thought to prevent LTP induced in layer VI under normal conditions. Cytochrome-oxidase staining after electrophysiological examination disclosed that LTP in layer IV of the freeze-lesioned cortex could only be elicited, when stimulation was applied within a preserved barrel cortex. Our study provides evidence that focal cryolesions during cortical development cause an impaired synaptic plasticity that may underlie learning disabilities.     

Preoperative localization of hand motor cortex by adaptive spatial filtering of magnetoencephalography data

OBJECT: The goal of this study was to examine the sensitivity and specificity in preoperative localization of hand motor cortex by imaging regional event-related desynchronization (ERD) of brainwaves in the beta frequency band (15-25 Hz) involved in self-paced movement. METHODS: Using magnetoencephalography (MEG), the authors measured ERD that occurred before self-paced unilateral index finger flexion in 66 patients with brain tumors, epilepsy, and arteriovenous malformations. RESULTS: The authors applied an adaptive spatial filtering algorithm to MEG data and found that peaks of the tomographic distribution of beta-band ERD sources reliably localized hand motor cortex compared with electrical cortical stimulation. They also observed high specificity in estimating contralateral hand motor cortical representations relative to somatosensory cortex. Neither presence nor location of tumor changed the qualitative or quantitative location of motor cortex relative to somatosensory cortex. CONCLUSIONS: An imaging protocol using ERD obtained by adaptive spatial filtering of MEG data can be used for extremely reliable preoperative localization of hand motor cortex.     

Correlation between patterns of horizontal connectivity and the extend of short-term representational plasticity in rat motor cortex

Plasticity of representational maps in adult cerebral cortex has been documented in both sensory and motor cortex, but the anatomical basis for cortical plasticity remains poorly understood. To investigate horizontal connectivity in primary motor cortex (M1) as a putative anatomical substrate for short-term, functional plasticity of adult motor cortical representations, a combination of electrical stimulation and biocytin labeling was used to examine pre-existing patterns of intrinsic connections in adult rat M1 in relationship to the pattern of reorganization of the motor movement may induced by transection of the contralateral facial nerve. Two hours after nerve cut, small, circumscribed regions of the forelimb representation expanded medially into territory previously devoted to the vibrissae representation. Outside of this novel, expanded forelimb region, no forelimb movement could be evoked from the former vibrissae representation at any time over the period of hours tested, thus representing silent cortex. Injections placed into vibrissae cortex representing the newly expanded forelimb representation gave rise to labeled axons and dense terminal fiber labeling which crossed the forelimb/vibrissae border and extended up to 1.2 mm within the low-threshold forelimb representation. In contrast, injections placed into silent vibrissae cortex gave rise to labeled axons and terminal boutons which remained mostly restricted to the original vibrissae representation, with only sparse projections that crossed into the low-threshold forelimb representation. Thus, these results suggest that the extent of short-term, functional reorganization of M1 induced within the first several hours following peripheral nerve cut is mediated, and constrained, by an anatomical framework of pre-existing, horizontal projections which traverse representation borders.      

Rapid cortical oscillations and early motor activity in premature human neonate

Delta-brush is the dominant pattern of rapid oscillatory activity (8-25 Hz) in the human cortex during the third trimester of gestation. Here, we studied the relationship between delta-brushes in the somatosensory cortex and spontaneous movements of premature human neonates of 29-31 weeks postconceptional age using a combination of scalp electroencephalography and monitoring of motor activity. We found that sporadic hand and foot movements heralded the appearance of delta-brushes in the corresponding areas of the cortex (lateral and medial regions of the contralateral central cortex, respectively). Direct hand and foot stimulation also reliably evoked delta-brushes in the same areas. These results suggest that sensory feedback from spontaneous fetal movements triggers delta-brush oscillations in the central cortex in a somatotopic manner. We propose that in the human fetus in utero, before the brain starts to receive elaborated sensory input from the external world, spontaneous fetal movements provide sensory stimulation and drive delta-brush oscillations in the developing somatosensory cortex contributing to the formation of cortical body maps.