Martin V. Sale

Cortisol Inhibits Neuroplasticity Induction in Human Motor Cortex

We investigated whether plasticity of human motor cortex (M1) is influenced by time of day, and whether changes in circulating levels of cortisol contribute to this effect. Neuroplasticity was induced using paired associative stimulation (PAS), involving electrical stimulation of left median nerve, paired with transcranial magnetic stimulation over the right M1 25 ms later (90 pairs at 0.05 Hz). Surface EMG was recorded from the left abductor pollicis brevis (APB) and first dorsal interosseous muscle. Cortisol levels were assessed from saliva. Time-of-day modulation of PAS effectiveness was assessed in 25 subjects who were tested twice, at 8:00 A.M. and 8:00 P.M. on separate days. In a second double-blind study, 17 subjects were tested with PAS at 8:00 P.M. on two occasions after administration of oral hydrocortisone (24 mg) or placebo. The motor-evoked potential (MEP) in resting APB increased significantly after PAS in the evening (when endogenous cortisol levels were low), but not in the morning. Oral hydrocortisone prevented facilitation of the APB MEP after PAS, and in the drug study, mean salivary cortisol levels were negatively associated with PAS effectiveness. The GABAB-mediated cortical silent period for APB was longer in the morning than in the evening, and was lengthened by PAS and oral hydrocortisone. We conclude that neuroplasticity in human M1 and GABAB-dependent intracortical inhibitory systems are influenced by time of day and modified by circulating levels of cortisol.

Is there a critical lesion site for unilateral spatial neglect? A meta-analysis using activation likelihood estimation

The critical lesion site responsible for the syndrome of unilateral spatial neglect has been debated for more than a decade. Here we performed an activation likelihood estimation (ALE) to provide for the first time an objective quantitative index of the consistency of lesion sites across anatomical group studies of spatial neglect. The analysis revealed several distinct regions in which damage has consistently been associated with spatial neglect symptoms. Lesioned clusters were located in several cortical and subcortical regions of the right hemisphere, including the middle and superior temporal gyrus, inferior parietal lobule, intraparietal sulcus, precuneus, middle occipital gyrus, caudate nucleus, and posterior insula, as well as in the white matter pathway corresponding to the posterior part of the superior longitudinal fasciculus. Further analyses suggested that separate lesion sites are associated with impairments in different behavioral tests, such as line bisection and target cancellation. Similarly, specific subcomponents of the heterogeneous neglect syndrome, such as extinction and allocentric and personal neglect, are associated with distinct lesion sites. Future progress in delineating the neuropathological correlates of spatial neglect will depend upon the development of more refined measures of perceptual and cognitive functions than those currently available in the clinical setting.

Visual attentional load influences plasticity in the human motor cortex.

Neural plasticity plays a critical role in learning, memory, and recovery from injury to the nervous system. Although much is known about the physical and physiological determinants of plasticity, little is known about the influence of cognitive factors. In this study, we investigated whether selective attention plays a role in modifying changes in neural excitability reflecting long-term potentiation (LTP)-like plasticity. We induced LTP-like effects in the hand area of the human motor cortex using transcranial magnetic stimulation (TMS). During the induction of plasticity, participants engaged in a visual detection task with either low or high attentional demands. Changes in neural excitability were assessed by measuring motor-evoked potentials in a small hand muscle before and after the TMS procedures. In separate experiments plasticity was induced either by paired associative stimulation (PAS) or intermittent theta-burst stimulation (iTBS). Because these procedures induce different forms of LTP-like effects, they allowed us to investigate the generality of any attentional influence on plasticity. In both experiments reliable changes in motor cortex excitability were evident under low-load conditions, but this effect was eliminated under high-attentional load. In a third experiment we investigated whether the attentional task was associated with ongoing changes in the excitability of motor cortex, but found no difference in evoked potentials across the levels of attentional load. Our findings indicate that in addition to their role in modifying sensory processing, mechanisms of attention can also be a potent modulator of cortical plasticity.

Imaging human brain networks to improve the clinical efficacy of non-invasive brain stimulation.

The flexible integration of segregated neural processes is essential to healthy brain function. Advances in neuroimaging techniques have revealed that psychiatric and neurological disorders are characterized by anomalies in the dynamic integration of widespread neural populations. Re-establishing optimal neural activity is an important component of the treatment of such disorders. Non-invasive brain stimulation is emerging as a viable tool to selectively restore both local and widespread neural activity in patients affected by psychiatric and neurological disorders. Importantly, the different forms of non-invasive brain stimulation affect neural activity in distinct ways, which has important ramifications for their clinical efficacy. In this review, we discuss how non-invasive brain stimulation techniques influence widespread neural integration across brain regions. We suggest that the efficacy of such techniques in the treatment of psychiatric and neurological conditions is contingent on applying the appropriate stimulation paradigm to restore specific aspects of altered neural integration.

Male human motor cortex stimulus-response characteristics are not altered by aging

Evidence suggests that there are aging-related changes in corticospinal stimulus-response curve characteristics in later life. However, there is also limited evidence that these changes may only be evident in postmenopausal women and not in men. This study compared corticospinal stimulus-response curves from a group of young men [19.8 ± 1.6 yr (range 17-23 yr)] and a group of old men [n = 18, aged 64.1 ± 5.0 yr (range 55-73 yr)]. Transcranial magnetic stimulation (TMS) over the contralateral motor cortex was used to evoke motor potentials at a range of stimulus intensities in the first dorsal interosseous muscle of each hand separately. There was no effect of age group or hemisphere (i.e., left vs. right motor cortex) on motor evoked potential (MEP) amplitude or any other stimulus-response characteristic. MEP variability was strongly modulated by resting motor threshold but not by age. M-wave (but not F-wave) amplitude was reduced in old men, but expressing MEP amplitude as a ratio of M-wave amplitude did not reveal any age-related differences in cortically evoked stimulus-response characteristics. We conclude that male corticospinal stimulus-response characteristics are not altered by advancing age and that previously reported age-related changes in motor cortical excitability assessed with TMS are likely due to changes inherent in the female participants only. Future studies are warranted to fully elucidate the relationship between, and functional significance of, changes in circulating neuroactive sex hormones and motor function in later life.

Testing for spatial neglect with line bisection and target cancellation: are both tasks really unrelated?

Damage to the parietal lobe can induce a condition known as spatial neglect, characterized by a lack of awareness of the personal and/or extrapersonal space opposite the damaged brain region. Spatial neglect is commonly assessed clinically using either the line bisection or the target cancellation task. However, it is unclear whether poor performance on each of these two tasks is associated with the same or different lesion locations. To date, methodological limitations and differences have prevented a definitive link between task performance and lesion location to be made. Here we report findings from a voxel-based lesion symptom mapping (VLSM) analysis of an unbiased selection of 44 patients with a recent unifocal stroke. Patients performed both the line bisection and target cancellation task. For each of the two tasks a continuous score was incorporated into the VLSM analysis. Both tasks correlated highly with each other (r = .76) and VLSM analyses indicated that the angular gyrus was the critical lesion site for both tasks. The results suggest that both tasks probe the same underlying cortical deficits and although the cancellation task was more sensitive than the line bisection task, both can be used in a clinical setting to test for spatial neglect.

A hierarchy of timescales explains distinct effects of local inhibition of primary visual cortex and frontal eye fields

Within the primate visual system, areas at lower levels of the cortical hierarchy process basic visual features, whereas those at higher levels, such as the frontal eye fields (FEF), are thought to modulate sensory processes via feedback connections. Despite these functional exchanges during perception, there is little shared activity between early and late visual regions at rest. How interactions emerge between regions encompassing distinct levels of the visual hierarchy remains unknown. Here we combined neuroimaging, non-invasive cortical stimulation and computational modelling to characterize changes in functional interactions across widespread neural networks before and after local inhibition of primary visual cortex or FEF. We found that stimulation of early visual cortex selectively increased feedforward interactions with FEF and extrastriate visual areas, whereas identical stimulation of the FEF decreased feedback interactions with early visual areas. Computational modelling suggests that these opposing effects reflect a fast-slow timescale hierarchy from sensory to association areas. DOI: http://dx.doi.org/10.7554/eLife.15252.001

Dissociable effects of local inhibitory and excitatory theta-burst stimulation on large-scale brain dynamics

Normal brain function depends on a dynamic balance between local specialization and large-scale integration. It remains unclear, however, how local changes in functionally specialized areas can influence integrated activity across larger brain networks. By combining transcranial magnetic stimulation with resting-state functional magnetic resonance imaging, we tested for changes in large-scale integration following the application of excitatory or inhibitory stimulation on the human motor cortex. After local inhibitory stimulation, regions encompassing the sensorimotor module concurrently increased their internal integration and decreased their communication with other modules of the brain. There were no such changes in modular dynamics following excitatory stimulation of the same area of motor cortex nor were there changes in the configuration and interactions between core brain hubs after excitatory or inhibitory stimulation of the same area. These results suggest the existence of selective mechanisms that integrate local changes in neural activity, while preserving ongoing communication between brain hubs.

Visual spatial attention has opposite effects on bidirectional plasticity in the human motor cortex

Long-term potentiation (LTP) and long-term depression (LTD) are key mechanisms of synaptic plasticity that are thought to act in concert to shape neural connections. Here we investigated the influence of visual spatial attention on LTP-like and LTD-like plasticity in the human motor cortex. Plasticity was induced using paired associative stimulation (PAS), which involves repeated pairing of peripheral nerve stimulation and transcranial magnetic stimulation to alter functional responses in the thumb area of the primary motor cortex. PAS-induced changes in cortical excitability were assessed using motor-evoked potentials. During plasticity induction, participants directed their attention to one of two visual stimulus streams located adjacent to each hand. When participants attended to visual stimuli located near the left thumb, which was targeted by PAS, LTP-like increases in excitability were significantly enhanced, and LTD-like decreases in excitability reduced, relative to when they attended instead to stimuli located near the right thumb. These differential effects on (bidirectional) LTP-like and LTD-like plasticity suggest that voluntary visual attention can exert an important influence on the functional organization of the motor cortex. Specifically, attention acts to both enhance the strengthening and suppress the weakening of neural connections representing events that fall within the focus of attention.

Increased intracortical inhibition in elderly adults with anterior-posterior current flow: a TMS study

OBJECTIVE All previous studies using TMS to assess short-interval intracortical inhibition (SICI) in older adults have used a conventional coil orientation, which produces posterior-to-anterior (PA) current flow in the motor cortex. However, no studies have examined SICI in older adults by reversing the coil to induce anterior-to-posterior (AP) current flow, which is considered more sensitive at detecting SICI. Therefore, we investigated age-related changes in SICI using both PA and AP TMS across different conditioning stimulus intensities and muscle activation states. METHODS In 22 young and 20 older adults, SICI was assessed using PA and AP coil orientations, across a range of conditioning stimulus intensities (70-90% active motor threshold), and whilst participants kept their first dorsal interosseous (FDI) muscle either relaxed or active (2N force). RESULTS There were no age-related differences in SICI using conventional PA TMS in resting or active FDI muscle. However, SICI was increased in elderly participants when assessed with reverse coil AP TMS in resting FDI. CONCLUSIONS Coil orientation is a key factor to consider when assessing age-related differences in SICI. SIGNIFICANCE Reverse coil AP TMS can reveal age-related changes in SICI, which were previously not evident with conventional PA TMS. This may have implications for the assessment of SICI in some clinical populations that may show subtle differences in SICI circuitry.