Fine-grained nociceptive maps in primary somatosensory cortex

Topographic maps of the receptive surface are a fundamental feature of neural organization in many sensory systems. While touch is finely mapped in the cerebral cortex, it remains controversial how precise any cortical nociceptive map may be. Given that nociceptive innervation density is relatively low on distal skin regions such as the digits, one might conclude that the nociceptive system lacks fine representation of these regions. Indeed, only gross spatial organization of nociceptive maps has been reported so far. However, here we reveal the existence of fine-grained somatotopy for nociceptive inputs to the digits in human primary somatosensory cortex (SI). Using painful nociceptive-selective laser stimuli to the hand, and phase-encoded fMRI analysis methods, we observed somatotopic maps of the digits in contralateral SI. These nociceptive maps were highly aligned with maps of non-painful tactile stimuli, suggesting comparable cortical representations for, and possible interactions between, mechanoreceptive and nociceptive signals. Our findings may also be valuable for future studies tracking the timecourse and the spatial pattern of plastic changes in cortical organization involved in chronic pain

Cortical plasticity in response to median nerve trauma

Median nerve injuries in adults, repaired with nerve suture, lead to incomplete functional recovery despite improved surgical technique. This results in a reduction in quality of life, poorer working ability and a considerable expense for society. Misrouting of axons at the suture site connects regenerating axons to the wrong distal end organs. When distorted signals are conveyed to the dorsal root ganglia, spinal cord, thalamus and the somatosensory cortex, somatotopic maps at all levels become reorganised in a disorderly fashion. Children often regain full sensory function after median nerve injury and repair despite impaired conduction across the injured segment. There is growing evidence that cortical plasticity is the main mechanism behind the superior recovery seen in young patients, but the exact pattern of reorganisation and its impact on functional recovery are not fully understood. The general aim of this thesis was to investigate various aspects of cortical plasticity, in particular the response to median nerve injury. To this end we used two non-invasive brain imaging techniques, functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). In Paper I we investigated the concept of audio-tactile interaction in a healthy population. We found an increased overlap between cortical activation areas (fMRI) in patients trained with coupled tactile and auditory stimuli indicating modulation of cortical plasticity induced by cross-modal training. In Paper II we studied ageand time-dependent effects on cortical activity patterns in patients with median nerve injury by correlating age at the time of injury and time passed since injury to sensory function, and cortical activation. We found a time-dependent decline in the size of the cortical activation area during stimulation of both the median and the ulnar nerve (fMRI). Furthermore, there was greater ipsilateral activation in the patient group than in a control group from a previous study. However, the results were not conclusive on this point because the stimulation paradigms differed between the two studies (event-related in the present and block paradigm in the previous study). Paper III was performed using MEG in order to further study cortical plasticity in patients with median nerve injury. We found decreased N1 and P1 amplitudes during stimulation of the injured median nerve, and an increase in these amplitudes during ulnar nerve stimulation. Paper IV was designed to reveal any possible differences in lateralisation of cortical activation after median nerve injury and to see if this was influenced by the stimulus paradigm used. By means of a laterality index (LI) the extent of contra- and ipsilateral activation was calculated. LI is decreased (more ipsilateral activation) in patients with a median nerve injury compared to controls. This means that median nerve injury causes a shift of activity from the contralateral to the ipsilateral SI. The type of stimulus paradigm (event-related or block) did not affect LI. Our findings add to the evolving knowledge of the cortical plasticity following median nerve injury

Brain (re)organisation following amputation:implications for phantom limb pain

Following arm amputation the region that represented the missing hand in primary somatosensory cortex (S1) becomes deprived of its primary input, resulting in changed boundaries of the S1 body map. This remapping process has been termed ‘reorganisation’ and has been attributed to multiple mechanisms, including increased expression of previously masked inputs. In a maladaptive plasticity model, such reorganisation has been associated with phantom limb pain (PLP). Brain activity associated with phantom hand movements is also correlated with PLP, suggesting that preserved limb functional representation may serve as a complementary process. Here we review some of the most recent evidence for the potential drivers and consequences of brain (re)organisation following amputation, based on human neuroimaging. We emphasise other perceptual and behavioural factors consequential to arm amputation, such as non-painful phantom sensations, perceived limb ownership, intact hand compensatory behaviour or prosthesis use, which have also been related to both cortical changes and PLP. We also discuss new findings based on interventions designed to alter the brain representation of the phantom limb, including augmented/virtual reality applications and brain computer interfaces. These studies point to a close interaction of sensory changes and alterations in brain regions involved in body representation, pain processing and motor control. Finally, we review recent evidence based on methodological advances such as high field neuroimaging and multivariate techniques that provide new opportunities to interrogate somatosensory representations in the missing hand cortical territory. Collectively, this research highlights the need to consider potential contributions of additional brain mechanisms, beyond S1 remapping, and the dynamic interplay of contextual factors with brain changes for understanding and alleviating PLP

Shifts of attention in the early blind: an ERP study of attentional control processes in the absence of visual spatial information

To investigate the role of visual spatial information in the control of spatial attention, event-related brain potentials (ERPs) were recorded during a tactile attention task for a group of totally blind participants who were either congenitally blind or had lost vision during infancy, and for an age-matched, sighted control group who performed the task in the dark. Participants had to shift attention to the left or right hand (as indicated by an auditory cue presented at the start of each trial) in order to detect infrequent tactile targets delivered to this hand. Effects of tactile attention on the processing of tactile events, as reflected by attentional modulations of somatosensory ERPs to tactile stimuli, were very similar for early blind and sighted participants, suggesting that the capacity to selectively process tactile information from one hand versus the other does not differ systematically between the blind and the sighted. ERPs measured during the cue–target interval revealed an anterior directing attention negativity (ADAN) that was present for the early blind group as well as for the sighted control group. In contrast, the subsequent posterior late direction attention negativity (LDAP) was absent in both groups. These results suggest that these two components reflect functionally distinct attentional control mechanisms which differ in their dependence on the availability of visually coded representations of external space

Perceptually relevant remapping of human somatotopy in 24 hours

Experience-dependent reorganisation of functional maps in the cerebral cortex is well described in the primary sensory cortices. However, there is relatively little evidence for such cortical reorganisation over the short-term. Using human somatosensory cortex as a model, we investigated the effects of a 24 hr gluing manipulation in which the right index and right middle fingers (digits 2 and 3) were adjoined with surgical glue. Somatotopic representations, assessed with two 7 tesla fMRI protocols, revealed rapid off-target reorganisation in the non-manipulated fingers following gluing, with the representation of the ring finger (digit 4) shifted towards the little finger (digit 5) and away from the middle finger (digit 3). These shifts were also evident in two behavioural tasks conducted in an independent cohort, showing reduced sensitivity for discriminating the temporal order of stimuli to the ring and little fingers, and increased substitution errors across this pair on a speeded reaction time task

Re-wiring the brain: Increased functional connectivity within primary somatosensory cortex following synchronous co-activation

AbstractThe primary somatosensory cortex shows precise topographical organisation, but can be quickly modified by alterations to sensory inputs. Temporally correlated sensory inputs to the digits can result in the merging of digit representations on the cortical surface. Underlying mechanisms driving these changes are unclear but the strengthening of intra-cortical synaptic connections via Hebbian mechanisms has been suggested. We use fMRI measures of temporal coherence to infer alterations in the relative strength of neuronal connections between digit regions 2 and 4 following 3hours of synchronous and asynchronous co-activation. Following synchronous co-activation we find a 20% increase in temporal coherence of the fMRI signal (p=0.0004). No significant change is seen following asynchronous co-activation suggesting that temporal coincidence between the two digit inputs during co-activation is driving this coherence change. In line with previous work we also find a trend towards reduced separation of the digit representations following synchronous co-activation and significantly increased separation for the asynchronous case. Increased coherence is significantly correlated with reduced digit separation for the synchronous case. This study shows that passive synchronous stimulation to the digits strengthens the underlying cortical connections between the digit regions in only a few hours, and that this mechanism may be related to topographical re-organisation

Perceptual abnormalities in amputees: phantom pain, mirror-touch synaesthesia and referred tactile sensations

It is often reported that after amputation people experience "a constant or inconstant... sensory ghost... faintly felt at time, but ready to be called up to [their] perception" (Mitchell, 1866). Perceptual abnormalities have been highlighted in amputees, such as sensations in the phantom when being stroked elsewhere (Ramachandran et al., 1992) or when observing someone in pain (Giummarra and Bradshaw, 2008). This thesis explored the perceptual changes that occur following amputation whist focusing on pain, vision and touch. A sample of over 100 amputees were recruited through the National Health Service. Despite finding no difference in phantom pain based on physical amputation details or nonpainful perceptual phenomena, results from Paper 1 indicated that phantom pain may be more intense, with sensations occurring more frequently, in amputees whose pain was triggerinduced. The survey in Paper 2 identified a group of amputees who in losing a limb acquired mirror-touch synaesthesia. Higher levels of empathy found in mirror-touch amputees might mean that some people are predisposed to develop synaesthesia, but that it takes sensory loss to bring dormant cross-sensory interactions into consciousness. Although the mirror-system may reach supra-threshold levels in some amputees, the experiments in Paper 3 suggested a relatively intact mirror-system in amputees overall. Specifically, in a task of apparent biological motion, amputees showed a similar, although weaker, pattern of results to normalbodied participants. The results of Paper 4 showed that tactile spatial acuity on the face was also largely not affected by amputation, as no difference was found between the sides ipsilateral and contralateral to the stump. In Paper 5 cross-modal cuing was used to investigate whether referred tactile sensations could prime a visually presented target in space occupied by the phantom limb. We conclude that perception is only moderately affected in most amputees, but that in some the sensory loss causes normally sub-threshold processing to enhance into conscious awareness

Cross sectional study to determine whether there are central nervous system changes in rugby players who have sustained recurrent ankle injuries

Background: Rugby is a popular game played around the world and has one of the highest recorded injury rates in sport. The literature exposes ankle injuries as one of the most common areas injured in sport and this trend carries through in rugby too, with lateral ankle sprains predominating. Recurrent ankle injuries are commonly reported in the literature and account for high economic and social burden. There are many intrinsic and extrinsic risk factors credited with causing lateral ankle injuries but to date the literature does not show conclusive evidence for management and prevention of recurrent injuries. A new area of research that has not previously been explored is the neurological influence on recurrent injury. Central processing is a recognised form of learning seen in adults and children during normal development and training and more recently acknowledged in injury settings. This phenomenon has also been seen in abnormal states of development such as neglect and chronic pain. Central Nervous System Changes In Recurrent Ankle Injuries In Rugby Player 2 Aim: The purpose of this study was to investigate whether there are changes in the central nervous system of rugby players with recurrent ankle injuries. Methods: An experimental and control group was used for this cross sectional study. Participants were recruited from the Golden Lions Rugby Union. Forty-six players in total were recruited. The control group consisted of 22 players, and the recurrent injury group consisted of 24 players. Medical and Sports History Questionnaire was administered as well as a battery of four physical test procedures. The questionnaire asked participants to provide information regarding demographics, playing position, training and playing history, current general health, current and previous injury history, and specifically ankle injury history. The four testing procedures were: body image testing, laterality testing, two point discrimination testing and pressure-pain threshold testing. Results: The results were collected and recorded. Between group and within group comparisons were made for the control and recurrent injury groups. From the Medical and Sports History Questionnaire the results indicated that the recurrent injury group participated in a significantly shorter preseason training period compared to the control group. The laterality testing within group analysis had a significant difference, the injured side had a slower recognition time [1.4(1.3-1.6)] compared to the uninjured side [1.3(1.15-1.5) Central Nervous System Changes In Recurrent Ankle Injuries In Rugby Player 3 p<0.01]. Pressure pain threshold testing produced a significant difference for the control group on the ATFL test site and the PTFL site. The PTFL site also demonstrated significant difference in the between group comparison analysis. The results from the two point discrimination testing and the body image testing produced interesting results. The two point discrimination tests performed on the both the recurrent injury group and the control group using within group comparison showed significant differences on the anterior talofibular ligament between the affected and nonaffected limbs. The between group test result were also significant for the injured vs control side at the ATFL site. The affected side showed a poorer ability to differentiate between one and two points, needing a bigger area before two points were distinguished from one. Similarly, body image testing showed significant differences in the within group comparison of total area drawn for the recurrent injury group only. In the recurrent injury group, the drawing of the affected foot was significantly larger than the drawing of the unaffected side. The control group showed no differences between sides. Conclusion: The study recommends that there is a relationship between central nervous system changes in recurrent ankle injuries in the sample group of professional rugby players. The data indicates that preseason length is a factor to be considered in recurrent ankle injuries. The clinical tests focussed specifically on central nervous system changes also produced some illuminating results. The recurrent injury group demonstrated significant difference between injured and uninjured sides in both two point discrimination testing of the ATFL ligaments and in the body image drawing of the foot and ankle. The control group in contrast didn't yield any differences between sides for these same tests. The pressure pain testing and laterality testing producing significant results also indicate the central nervous system involvement in recurrent injury

Reorganisation of sensorimotor function in children with brain disease

Introduction: In this study, paradigms were developed for the investigation of sensorimotor function in children using functional MRI (fMRI), somatosensory evoked potential (SEP) recordings and behavioural measures. These techniques were applied both to normal controls subjects and to children with brain disease. A major aim was to investigate the remarkable recovery of function that can take place following brain injury sustained early in life. Methods: Three fMRI paradigms were developed, namely active movement of the hand, passive flexion/extension movement of the fingers and median nerve stimulation. In addition, SEPs of functional cortical responses to stimulation of the median nerve were recorded at high temporal resolution. Finally, the extent of residual or recovered sensory and motor hand function was assessed using behavioural tests, including grip strength and double simultaneous stimulation. In one set of investigations, all three techniques were applied to children following hemispherectomy or children following vascular damage to the middle cerebral artery territory, to examine the pattern of residual sensorimotor function following brain injury. In a second study, fMRI was carried out in pre-surgical paediatric patients for mapping of the sensorimotor cortex in preparation for surgical resection of lesions in the vicinity of this cortical region. Results and Discussion: fMRI was successful in locating the hand cortical sensorimotor area in 11 out of 12 paediatric patients pre-operatively, and was of value to the neurosurgeon in helping to delineate the boundaries of subsequent cortical resection. In patients following stroke and hemispherectomy, a combination of fMRI, SEP and behavioural techniques provided evidence for inter-hemispheric reorganisation of sensorimotor function through ipsilateral sensorimotor pathways, and also suggested an increase in the involvement of ipsilateral secondary sensorimotor areas. The data also indicate that cortical sensorimotor reorganisation and functional recovery can be seen in patient both with congenital disease and with late-onset acquired disease, suggesting that factors additional to age at injury may influence the degree of residual function resulting from cerebral reorganisation. Informed consent was obtained for all patients and controls, and the study was approved by the Great Ormond Street Hospital for Children/Institute of Child Health Research Ethics Committee