Multifactorial determinants of the neurocognitive effects of electroconvulsive therapy

For many patients with neuropsychiatric illnesses, standard psychiatric treatments with mono or combination pharmacotherapy, psychotherapy, and transcranial magnetic stimulation are ineffective. For these patients with treatment-resistant neuropsychiatric illnesses, a main therapeutic option is electroconvulsive therapy (ECT). Decades of research have found ECT to be highly effective; however, it can also result in adverse neurocognitive effects. Specifically, ECT results in disorientation after each session, anterograde amnesia for recently learned information, and retrograde amnesia for previously learned information. Unfortunately, the neurocognitive effects and underlying mechanisms of action of ECT remain poorly understood. The purpose of this paper was to synthesize the multiple moderating and mediating factors that are thought to underlie the neurocognitive effects of ECT into a coherent model. Such factors include demographic and neuropsychological characteristics, neuropsychiatric symptoms, ECT technical parameters, and ECT-associated neurophysiological changes. Future research is warranted to evaluate and test this model, so that these findings may support the development of more refined clinical seizure therapy delivery approaches and efficacious cognitive remediation strategies to improve the use of this important and widely used intervention tool for neuropsychiatric diseases. Copyright © 2014 by Lippincott Williams & Wilkins.

Phasic modulation of corticomotor excitability during passive movement of the upper limb: effects of movement frequency and muscle specificity

Modulations in the excitability of spinal reflex pathways during passive rhythmic movements of the lower limb have been demonstrated by a number of previous studies [4]. Less emphasis has been placed on the role of supraspinal pathways during passive movement, and on tasks involving the upper limb. In the present study, transcranial magnetic stimulation (TMS) was delivered to subjects while undergoing passive flexion-extension movements of the contralateral wrist. Motor evoked potentials (MEPs) of flexor carpi radialis (FCR) and abductor pollicus brevis (APB) muscles were recorded. Stimuli were delivered in eight phases of the movement cycle during three different frequencies of movement. Evidence of marked modulations in pathway excitability was found in the MEP amplitudes of the FCR muscle, with responses inhibited and facilitated from static values in the extension and flexion phases, respectively. The results indicated that at higher frequencies of movement there was greater modulation in pathway excitability. Paired-pulse TMS (sub-threshold conditioning) at short interstimulus intervals revealed modulations in the extent of inhibition in MEP amplitude at high movement frequencies. In the APE muscle, there was some evidence of phasic modulations of response amplitude, although the effects were less marked than those observed in FCR. It is speculated that these modulatory effects are mediated via Ia afferent pathways and arise as a consequence of the induced forearm muscle shortening and lengthening. Although the level at which this input influences the corticomotoneuronal pathway is difficult to discern, a contribution from cortical regions is suggested. (C) 2001 Published by Elsevier Science B.V.

Dual-task interference: Attentional and neurophysiological influences

Performing two tasks simultaneously often degrades performance of one or both tasks. While this dual-task interference is classically interpreted in terms of shared attentional resources, where two motor tasks are performed simultaneously interactions within primary motor cortex (i.e., activity-dependent coupling) may also be a contributing factor. In the present study TMS (transcranial magnetic stimulation) was used to examine the contribution of activity-dependent coupling to dual-task interference during concurrent performance of a bimanual coordination task and a discrete probe reaction time (RT) task involving the foot. Experiments 1 and 2 revealed that activity-dependent coupling within the leg corticomotor pathway was greater during dual-task performance than single-task performance, and this was associated with interference on the probe RT task (i.e., increased RT). Experiment 3 revealed that dual-task interference occurred regardless of whether the dual-task involved two motor tasks or a motor and cognitive task, however activity-dependent coupling was present only when a dual motor task was performed. This suggests that activity-dependent coupling is less detrimental to performance than attentional processes operating upstream of the corticomotor system. Finally, while prioritising the RT task reduced, but did not eliminate, dual-task interference the contribution of activity-dependent coupling to dual-task interference was not affected by task prioritisation. This suggests that although activity-dependent coupling may contribute to dual motor-task interference, attentional processes appear to be more important. It also suggests that activity-dependent coupling may not be subject to modulation by attentional processes. (C) 2009 Elsevier B.V. All rights reserved.

Vision Modulates Corticospinal Suppression in a Functionally Specific Manner during Movement of the Opposite Limb

The effect of vision on the excitability of corticospinal projections to the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles of right human forearm was investigated before and during discrete movement of the opposite limb. An external force opposed the initial phase of the movement (wrist flexion) and assisted the reverse phase, so that recruitment of the wrist extensors was minimized. Three conditions were used as follows: viewing the inactive right limb (Vision), viewing the mirror image of the moving left limb (Mirror), and with vision of the right limb occluded (No Vision). Transcranial magnetic stimulation was delivered to the left motor cortex: before, at the onset of, or during the left limb movement to obtain motor evoked potentials (MEPs) in the muscles of the right forearm. At and following movement onset, MEPs obtained in the right FCR were smaller in the Vision condition than in the Mirror and No Vision conditions. A distinct pattern of variation was obtained for the ECR. In all conditions, MEPs in this muscle were elevated upon or following movement of the opposite limb. An additional analysis of ipsilateral silent periods indicated that interhemispheric inhibition plays a role in mediating these effects. Activity-dependent changes in corticospinal output to a resting limb during discrete actions of the opposite limb are thus directly contingent upon where one looks. Furthermore, the extent to which vision exerts an influence upon projections to specific muscles varies in accordance with the functional contribution of their homologs to the intended action.

Training-induced modifications of corticospinal reactivity in severely affected stroke survivors

When permitted access to the appropriate forms of rehabilitation, many severely affected stroke survivors demonstrate a capacity for upper limb functional recovery well in excess of that formerly considered possible. Yet, the mechanisms through which improvements in arm function occur in such profoundly impaired individuals remain poorly understood. An exploratory study was undertaken to investigate the capacity for brain plasticity and functional adaptation, in response to 12-h training of reaching using the SMART Arm device, in a group of severely affected stroke survivors with chronic upper limb paresis. Twenty-eight stroke survivors were enroled. Eleven healthy adults provided normative data. To assess the integrity of ipsilateral and contralateral corticospinal pathways, transcranial magnetic stimulation was applied to evoke responses in triceps brachii during an elbow extension task. When present, contralateral motor-evoked potentials (MEPs) were delayed and reduced in amplitude compared to those obtained in healthy adults. Following training, contralateral responses were more prevalent and their average onset latency was reduced. There were no reliable changes in ipsilateral MEPs. Stroke survivors who exhibited contralateral MEPs prior to training achieved higher levels of arm function and exhibited greater improvements in performance than those who did not initially exhibit contralateral responses. Furthermore, decreases in the onset latency of contralateral MEPs were positively related to improvements in arm function. Our findings demonstrate that when severely impaired stroke survivors are provided with an appropriate rehabilitation modality, modifications of corticospinal reactivity occur in association with sustained improvements in upper limb function.

Anticipatory Planning Reveals Segmentation of Cortical Motor Output During Action Observation

It has been argued that the variation in brain activity that occurs when observing another person reflects a representation of actions that is indivisible, and which plays out in full once the intent of the actor can be discerned. We used transcranial magnetic stimulation to probe the excitability of corticospinal projections to 2 intrinsic hand muscles while motions to reach and grasp an object were observed. A symbolic cue either faithfully indicated the required final orientation of the object and thus the nature of the grasp that was required, or was in conflict with the movement subsequently displayed. When the cue was veridical, modulation of excitability was in accordance with the functional role of the muscles in the action observed. If however the cue had indicated that the alternative grasp would be required, modulation of output to first dorsal interosseus was consistent with the action specified, rather than the action observed-until the terminal phase of the motion sequence during which the object was seen lifted. Modulation of corticospinal output during observation is thus segmented-it progresses initially in accordance with the action anticipated, and if discrepancies are revealed by visual input, coincides thereafter with that of the action seen.

Human parietal and primary motor cortical interactions are selectively modulated during the transport and grip formation of goal-directed hand actions

Posterior parietal cortex (PPC) constitutes a critical cortical node in the sensorimotor system in which goal-directed actions are computed. This information then must be transferred into commands suitable for hand movements to the primary motor cortex (M1). Complexity arises because reach-to-grasp actions not only require directing the hand towards the object (transport component), but also preshaping the hand according to the features of the object (grip component). Yet, the functional influence that specific PPC regions exert over ipsilateral M1 during the planning of different hand movements remains unclear in humans. Here we manipulated transport and grip components of goal-directed hand movements and exploited paired-pulse transcranial magnetic stimulation (ppTMS) to probe the functional interactions between M1 and two different PPC regions, namely superior parieto-occipital cortex (SPOC) and the anterior region of the intraparietal sulcus (aIPS), in the left hemisphere. We show that when the extension of the arm is required to contact a target object, SPOC selectively facilitates motor evoked potentials, suggesting that SPOC-M1 interactions are functionally specific to arm transport. In contrast, a different pathway, linking the aIPS and ipsilateral M1, shows enhanced functional connections during the sensorimotor planning of grip. These results support recent human neuroimaging findings arguing for specialized human parietal regions for the planning of arm transport and hand grip during goal-directed actions. Importantly, they provide new insight into the causal influences these different parietal regions exert over ipsilateral motor cortex for specific types of planned hand movements

Characterizing changes in the excitability of corticospinal projections to proximal muscles of the upper limb

Background: There has been an explosion of interest in methods of exogenous brain stimulation that induce changes in the excitability of human cerebral cortex. The expectation is that these methods may promote recovery of function following brain injury. To assess their effects on motor output, it is typical to assess the state of corticospinal projections from primary motor cortex to muscles of the hand, via electromyographic responses to transcranial magnetic stimulation. If a range of stimulation intensities is employed, the recruitment curves (RCs) obtained can, at least for intrinsic hand muscles, be fitted by a sigmoid function.

Objective/hypothesis: To establish whether sigmoid fits provide a reliable basis upon which to characterize the input–output properties of the corticospinal pathway for muscles proximal to the hand, and to assess as an alternative the area under the (recruitment) curve (AURC).

Methods: A comparison of the reliability of these measures, using RCs obtained for muscles that are frequently the targets of rehabilitation.

Results: The AURC is an extremely reliable measure of the state of corticospinal projections to hand and forearm muscles, which has both face and concurrent validity. Construct validity is demonstrated by detection of widely distributed (across muscles) changes in corticospinal excitability induced by paired associative stimulation (PAS).

Conclusion(s): The parameters derived from sigmoid fits are unlikely to provide an adequate means to assess the effectiveness of therapeutic regimes. The AURC can be employed to characterize corticospinal projections to a range of muscles, and gauge the efficacy of longitudinal interventions in clinical rehabilitation.

The effects of TMS over dorsolateral prefrontal cortex on trans-saccadic memory of multiple objects

Humans typically make several rapid eye movements (saccades) per second. It is thought that visual working memory can retain and spatially integrate three to four objects or features across each saccade but little is known about this neural mechanism. Previously we showed that transcranial magnetic stimulation (TMS) to the posterior parietal cortex and frontal eye fields degrade trans-saccadic memory of multiple object features (Prime, Vesia, & Crawford, 2008, Journal of Neuroscience, 28(27), 6938-6949; Prime, Vesia, & Crawford, 2010, Cerebral Cortex, 20(4), 759-772.). Here, we used a similar protocol to investigate whether dorsolateral prefrontal cortex (DLPFC), an area involved in spatial working memory, is also involved in trans-saccadic memory. Subjects were required to report changes in stimulus orientation with (saccade task) or without (fixation task) an eye movement in the intervening memory interval. We applied single-pulse TMS to left and right DLPFC during the memory delay, timed at three intervals to arrive approximately 100ms before, 100ms after, or at saccade onset. In the fixation task, left DLPFC TMS produced inconsistent results, whereas right DLPFC TMS disrupted performance at all three intervals (significantly for presaccadic TMS). In contrast, in the saccade task, TMS consistently facilitated performance (significantly for left DLPFC/perisaccadic TMS and right DLPFC/postsaccadic TMS) suggesting a dis-inhibition of trans-saccadic processing. These results are consistent with a neural circuit of trans-saccadic memory that overlaps and interacts with, but is partially separate from the circuit for visual working memory during sustained fixation.

Tele-Supervised FES-Assisted Exercise for Hemiplegic Upper Limb

Stroke survivors often have upper limb (UL) hemiparesis, limiting their ability to perform activities of daily life (ADLs). Intensive, task-oriented exercise therapy (ET) can improve UL function, but motivation to perform sufficient ET is difficult to maintain. Here we report on a trial in which a workstation was deployed in the homes of chronic stroke survivors to enable tele-coaching of ET in the guise of computer games. Participants performed 6 weeks of 1 hour/day, 5 days/week ET. Hand opening and grasp were assisted with functional electrical stimulation (FES). The primary outcome measure was the Action Research Arm Test (ARAT). Secondary outcome measures included a quantitative test of UL function performed on the workstation, grasp force measurements and transcranial magnetic stimulation (TMS). Improvements were seen in the functional tests, but surprisingly, not in the TMS responses. An important finding was that participants commencing with intermediate functional scores improved the most.

CONCLUSIONS: 1) Daily, tele-supervised FES-ET in chronic stroke survivors is feasible with commercially-available technology. 2) The intervention can significantly improve UL function, particularly in people who start with an intermediate level of function. 3) Significant improvements in UL function can occur in the absence of changes in TMS responses.

Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective

The brain derived neurotrophic factor (BDNF) Val66Met polymorphism and stimulation duration are thought to play an important role in modulating motor cortex plasticity induced by non-invasive brain stimulation (NBS). In the present study we sought to determine whether these factors interact or exert independent effects in older adults. Fifty-four healthy older adults (mean age = 66.85 years) underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS), applied over left M1 for either 10 or 20 min. Single pulse transcranial magnetic stimulation (TMS) was used to assess corticospinal excitability (CSE) before and every 5 min for 30 min following atDCS. On a group level, there was an interaction between stimulation duration and BDNF genotype, with Met carriers (n = 13) showing greater post-intervention potentiation of CSE compared to Val66Val homozygotes homozygotes (n = 37) following 20 min (p = 0.002) but not 10 min (p = 0.219) of stimulation. Moreover, Met carriers, but not Val/Val homozygotes, exhibited larger responses to TMS (p = 0.046) after 20 min atDCS, than following 10 min atDCS. On an individual level, two-step cluster analysis revealed a considerable degree of inter-individual variability, with under half of the total sample (42%) showing the expected potentiation of CSE in response to atDCS across both sessions. Intra-individual variability in response to different durations of atDCS was also apparent, with one-third of the total sample (34%) exhibiting LTP-like effects in one session but LTD-like effects in the other session. Both the inter-individual (p = 0.027) and intra-individual (p = 0.04) variability was associated with BDNF genotype. In older adults, the BDNF Val66Met polymorphism along with stimulation duration appears to play a role in modulating tDCS-induced motor cortex plasticity. The results may have implications for the design of NBS protocols for healthy and diseased aged populations.

Role of early visual cortex in trans-saccadic memory of object features

Early visual cortex (EVC) participates in visual feature memory and the updating of remembered locations across saccades, but its role in the trans-saccadic integration of object features is unknown. We hypothesized that if EVC is involved in updating object features relative to gaze, feature memory should be disrupted when saccades remap an object representation into a simultaneously perturbed EVC site. To test this, we applied transcranial magnetic stimulation (TMS) over functional magnetic resonance imaging-localized EVC clusters corresponding to the bottom left/right visual quadrants (VQs). During experiments, these VQs were probed psychophysically by briefly presenting a central object (Gabor patch) while subjects fixated gaze to the right or left (and above). After a short memory interval, participants were required to detect the relative change in orientation of a re-presented test object at the same spatial location. Participants either sustained fixation during the memory interval (fixation task) or made a horizontal saccade that either maintained or reversed the VQ of the object (saccade task). Three TMS pulses (coinciding with the pre-, peri-, and postsaccade intervals) were applied to the left or right EVC. This had no effect when (a) fixation was maintained, (b) saccades kept the object in the same VQ, or (c) the EVC quadrant corresponding to the first object was stimulated. However, as predicted, TMS reduced performance when saccades (especially larger saccades) crossed the remembered object location and brought it into the VQ corresponding to the TMS site. This suppression effect was statistically significant for leftward saccades and followed a weaker trend for rightward saccades. These causal results are consistent with the idea that EVC is involved in the gaze-centered updating of object features for trans-saccadic memory and perception.

Characteristics of Corticospinal Projections to the Intrinsic Hand Muscles in Skilled Harpists.

The process of learning to play a musical instrument necessarily alters the functional organisation of the cortical motor areas that are involved in generating the required movements. In the case of the harp, the demands placed on the motor system are quite specific. During performance, all digits with the sole exception of the little finger are used to pluck the strings. With a view to elucidating the impact of having acquired this highly specialized musical skill on the characteristics of corticospinal projections to the intrinsic hand muscles, focal transcranial magnetic stimulation (TMS) was used to elicit motor evoked potentials (MEPs) in three muscles (of the left hand): abductor pollicis brevis (APB); first dorsal interosseous (FDI); and abductor digiti minimi (ADM) in seven harpists. Seven non-musicians served as controls. With respect to the FDI muscle–which moves the index finger, the harpists exhibited reliably larger MEP amplitudes than those in the control group. In contrast, MEPs evoked in the ADM muscle–which activates the little finger, were smaller in the harpists than in the non-musicians. The locations on the scalp over which magnetic stimulation elicited discriminable responses in ADM also differed between the harpists and the non-musicians. This specific pattern of variation in the excitability of corticospinal projections to these intrinsic hand muscles exhibited by harpists is in accordance with the idiosyncratic functional demands that are imposed in playing this instrument.

Timing of response differentiation in human motor cortex during a speeded Go/No-go task

We explored the brain's ability to quickly prevent a pre-potent but unwanted motor response. To address this, transcranial magnetic stimulation was delivered over the motor cortex (hand representation) to probe excitability changes immediately after somatosensory cues prompted subjects to either move as fast as possible or withhold movement. Our results showed a difference in motor cortical excitability 90 ms post-stimulus contingent on cues to either promote or prevent movement. We suggest that our study design emphasizing response speed coupled with well-defined early probes allowed us to extend upon similar past investigations into the timing of response inhibition.

Neural adaptations associated with interlimb transfer in a ballistic wrist flexion task.

Cross education is the process whereby training of one limb gives rise to increases in the subsequent performance of its opposite counterpart. The execution of many unilateral tasks is associated with increased excitability of corticospinal projections from primary motor cortex (M1) to the opposite limb. It has been proposed that these effects are causally related. Our aim was to establish whether changes in corticospinal excitability arising from prior training of the opposite limb determine levels of interlimb transfer.

We used three vision conditions shown previously to modulate the excitability of corticospinal projections to the inactive (right) limb during wrist flexion movements performed by the training (left) limb. These were: mirrored visual feedback of the training limb; no visual feedback of either limb; and visual feedback of the inactive limb. Training comprised 300 discrete, ballistic wrist flexion movements executed as rapidly as possible. Performance of the right limb on the same task was assessed prior to, at the mid point of, and following left limb training.

There was no evidence that variations in the excitability of corticospinal projections (assessed by transcranial magnetic stimulation (TMS)) to the inactive limb were associated with, or predictive of, the extent of interlimb transfer that was expressed. There were however associations between alterations in muscle activation dynamics observed for the untrained limb, and the degree of positive transfer that arose from training of the opposite limb.

The results suggest that the acute adaptations that mediate the bilateral performance gains realised through unilateral practice of this ballistic wrist flexion task are mediated by neural elements other than those within M1 that are recruited at rest by single-pulse TMS.