Methods matter: A primer on permanent and reversible interference techniques in animals for investigators of human neuropsychology.

The study of patients with brain lesions has contributed greatly to our understanding of the biological bases of human cognition, but this approach also has several unavoidable limitations. Research that uses animal models complements and extends human neuropsychology by addressing many of these limitations. In this review, we provide an overview of permanent and reversible animal lesion techniques for researchers of human neuropsychology, with the aim of highlighting how these methods provide a valuable adjunct to behavioural, neuroimaging, physiological, and clinical investigations in humans. Research in animals has provided important lessons about how the limitations of one or more techniques, or differences in their mechanism of action, has impacted upon the understanding of brain organisation and function. These cautionary tales highlight the importance of striving for a thorough understanding of how any intereference technique works (whether in animal or human), and for how to best use animal research to clarify the precise mechanisms underlying temporary lesion methods in humans

Tactile gap detection deteriorates during bimanual symmetrical movements under mirror visual feedback

It has been suggested that incongruence between signals for motor intention and sensory input can cause pain and other sensory abnormalities. This claim is supported by reports that moving in an environment of induced sensorimotor conflict leads to elevated pain and sensory symptoms in those with certain painful conditions. Similar procedures can lead to reports of anomalous sensations in healthy volunteers too. In the present study, we used mirror visual feedback to investigate the effects of sensorimotor incongruence on responses to stimuli that arise from sources external to the body, in particular, touch. Incongruence between the sensory and motor signals for the right arm was manipulated by having the participants make symmetrical or asymmetrical movements while watching a reflection of their left arm in a parasagittal mirror, or the left hand surface of a similarly positioned opaque board. In contrast to our prediction, sensitivity to the presence of gaps in tactile stimulation of the right forearm was not reduced when participants made asymmetrical movements during mirror visual feedback, as compared to when they made symmetrical or asymmetrical movements with no visual feedback. Instead, sensitivity was reduced when participants made symmetrical movements during mirror visual feedback relative to the other three conditions. We suggest that small discrepancies between sensory and motor information, as they occur during mirror visual feedback with symmetrical movements, can impair tactile processing. In contrast, asymmetrical movements with mirror visual feedback may not impact tactile processing because the larger discrepancies between sensory and motor information may prevent the integration of these sources of information. These results contrast with previous reports of anomalous sensations during exposure to both low and high sensorimotor conflict, but are nevertheless in agreement with a forward model interpretation of perceptual modulations during goal directed movement.</p

Predictors of Self-Reported Neglect-like Symptoms and Involuntary Movements in Complex Regional Pain Syndrome Compared to Other Chronic Limb Pain Conditions

OBJECTIVE: In addition to pain, people with complex regional pain syndrome (CRPS) often report inattention to and disengagement from their affected limb (i.e., "neglect-like symptoms"). Understanding how these symptoms relate to other characteristics of CRPS, and chronic pain generally, could provide insights for preventing and treating CRPS. METHODS: We administered an online survey to people who received a diagnosis of CRPS (n = 335) and other chronic limb pain (n = 407). Neglect-like symptoms were assessed using the Neurobehavioral questionnaire. RESULTS: A principal component analysis identified two components: motor and cognitive neglect-like symptoms, and involuntary movements. Internal consistency of the components was acceptable. We conducted regression analyses with these as outcomes. Having CRPS, a painful lower limb, higher pain intensity, and somatic symptoms were associated with more motor and cognitive neglect-like symptoms. Having CRPS, higher pain intensity, depression, and somatic symptoms were associated with more involuntary movements. Age, gender, anxiety, disease duration, hours of pain per day, affected side, whether the limb was the most painful body part, and number of pain-related medical diagnoses were no predictors. Finally, motor and cognitive neglect-like symptoms were related to tremor; and involuntary movements to changes in skin color, swelling, sweating, toenails, weakness, and tremor. CONCLUSIONS: This study confirms the specificity of inattention to and disengagement from the affected limb in CRPS, independent of other factors. Furthermore, two components of the Neurobehavioral questionnaire were disentangled: motor and cognitive neglect-like symptoms, and involuntary movements. Results could potentially help clinicians to better assess neglect-like symptoms in chronic pain

Patients with lesions to the intraparietal cortex show greater proprioceptive realignment after prism adaptation:Evidence from open-loop pointing and manual straight ahead

Reaching toward a target viewed through laterally refracting prisms results in adaptation of both visual and (limb) proprioceptive spatial representations. Common ways to measure adaptation after-effect are to ask a person to point straight ahead with their eyes closed ("manual straight ahead", MSA), or to a seen target using their unseen hand ("open-loop pointing", OLP). MSA measures changes in proprioception only, whereas OLP measures the combined visual and proprioceptive shift. The behavioural and neurological mechanisms of prism adaptation have come under scrutiny following reports of reduced hemispatial neglect in patients following this procedure. We present evidence suggesting that shifts in proprioceptive spatial representations induced by prism adaptation are larger following lesions to the intraparietal cortex - a brain region that integrates retinotopic visual signals with signals of eye position in the orbit and that is activated during prism adaptation. Six healthy participants and six patients with unilateral intraparietal cortex lesions underwent prism adaptation. After-effects were measured with OLP and MSA. After-effects of control participants were larger when measured with OLP than with MSA, consistent with previous research and with the additional contribution of visual shift to OLP after-effects. However, patients' OLP shifts were not significantly different to their MSA shifts. We conclude that, for the patients, correction of pointing errors during prism adaptation involved proportionally more changes to arm proprioception than for controls. Since lesions to intraparietal cortex led to enhanced realignment of arm proprioceptive representations, our results indirectly suggest that the intraparietal cortex could be key for visual realignment.</p

Patients with lesions to the intraparietal cortex show greater proprioceptive realignment after prism adaptation:Evidence from open-loop pointing and manual straight ahead

Reaching toward a target viewed through laterally refracting prisms results in adaptation of both visual and (limb) proprioceptive spatial representations. Common ways to measure adaptation after-effect are to ask a person to point straight ahead with their eyes closed ("manual straight ahead", MSA), or to a seen target using their unseen hand ("open-loop pointing", OLP). MSA measures changes in proprioception only, whereas OLP measures the combined visual and proprioceptive shift. The behavioural and neurological mechanisms of prism adaptation have come under scrutiny following reports of reduced hemispatial neglect in patients following this procedure. We present evidence suggesting that shifts in proprioceptive spatial representations induced by prism adaptation are larger following lesions to the intraparietal cortex - a brain region that integrates retinotopic visual signals with signals of eye position in the orbit and that is activated during prism adaptation. Six healthy participants and six patients with unilateral intraparietal cortex lesions underwent prism adaptation. After-effects were measured with OLP and MSA. After-effects of control participants were larger when measured with OLP than with MSA, consistent with previous research and with the additional contribution of visual shift to OLP after-effects. However, patients' OLP shifts were not significantly different to their MSA shifts. We conclude that, for the patients, correction of pointing errors during prism adaptation involved proportionally more changes to arm proprioception than for controls. Since lesions to intraparietal cortex led to enhanced realignment of arm proprioceptive representations, our results indirectly suggest that the intraparietal cortex could be key for visual realignment.</p

Visual sensitivity in Complex Regional Pain Syndrome and fibromyalgia: an online study

Perceptual anomalies can provide insights into underlying pathologies even when they are not the main symptom of many clinical conditions. Complex regional pain syndrome (CRPS) and fibromyalgia are chronic pain conditions associated with changes in the central nervous system, possibly leading to enhanced visual sensitivity. It is unclear whether this occurs more than for people with other types of pain. We examined visual sensitivity elicited by different stimuli and in daily life, through an online study of people with CRPS (n = 57), fibromyalgia (n = 74), other pain (n = 50), and no pain (n = 89). Respondents rated changes in pain, discomfort, or distress from viewing patterns with different spatial frequencies (lower-order visual processing), and reversible figures (bistable images; higher-order visual processing). We assessed visual sensitivity in daily life using the Leiden Visual Sensitivity Scale and Visual Discomfort Scale. Respondents with CRPS or fibromyalgia reported more visual discomfort than pain-related and pain-free controls while viewing striped patterns and a circle, with no effect of spatial frequency. They reported more pain while viewing a nonreversible square, but not reversible figures (Necker Cube, Duck/Rabbit). Finally, they reported more daily visual sensitivity than pain-related and pain-free controls. Suppressing visual cortical activity might benefit people with CRPS or fibromyalgia

Validation of the Leiden Visual Sensitivity Scale and Visual Discomfort Scale in Chronic Pain Conditions

Discomfort provoked by normally innocuous visual stimuli has been reported by people with chronic pain. Visual discomfort may be higher in pain conditions in which central sensitization is implicated, such as Complex Regional Pain Syndrome (CRPS) and fibromyalgia. In an online study, we validated the Leiden Visual Sensitivity Scale (L-VISS) and Visual Discomfort Scale (VDS) in people with CRPS (n = 57), fibromyalgia (n = 75), and general chronic pain (n = 53); investigated whether these groups and pain-free controls (n = 125) differed in visual discomfort; and evaluated the effect of age. The L-VISS and VDS had good internal consistency. Both scales were positively related with experimentally induced visual distortions for mid-spatial frequency striped patterns, suggesting good construct validity. The scales were positively related with each other, and dissociated between the pain and pain-free groups in similar ways, suggesting good construct validity. There was no relationship between age and L-VISS scores and a small negative relationship between age and VDS scores. Visual discomfort was highest in the fibromyalgia group, followed by the CRPS group. This research confirms the utility of the L-VISS and VDS for measuring visual sensitivity in chronic pain and adds to evidence that central sensitization is an important mechanism of visual discomfort

Exploring bias in horizontal and vertical spatial representations using mental number lines and the greyscales task

People have a leftward bias when making visuospatial judgements about horizontally arranged stimuli (“pseudoneglect”), and a superior bias when making visuospatial judgements about vertically arranged stimuli. The leftward visuospatial bias in physical space seems to extend to the mental representation of space. However, whether any bias exists in mental representation of vertical space is unknown. We investigated whether people show a visuospatial bias in the mental representation of vertical space, and if any bias in mental representations of horizontal and vertical space related to the extent of bias in physical space. Participants (n=171) were presented with three numbers and asked which interval was smaller/larger (counterbalanced): the interval between the first and middle, or middle and last number. Participants were instructed to either think of the numbers as houses on a street or as floors of a building, or were given no imagery instructions. Participants in the houses on a street condition showed a leftward bias, but there was no superior bias in the floors of a building condition. In contrast, we replicated previous findings of leftward and superior bias on greyscales tasks. Our findings reinforce previous evidence that numbers are represented horizontally and ascending left to right by default

Tactile gap detection deteriorates during bimanual symmetrical movements under mirror visual feedback

It has been suggested that incongruence between signals for motor intention and sensory input can cause pain and other sensory abnormalities. This claim is supported by reports that moving in an environment of induced sensorimotor conflict leads to elevated pain and sensory symptoms in those with certain painful conditions. Similar procedures can lead to reports of anomalous sensations in healthy volunteers too. In the present study, we used mirror visual feedback to investigate the effects of sensorimotor incongruence on responses to stimuli that arise from sources external to the body, in particular, touch. Incongruence between the sensory and motor signals for the right arm was manipulated by having the participants make symmetrical or asymmetrical movements while watching a reflection of their left arm in a parasagittal mirror, or the left hand surface of a similarly positioned opaque board. In contrast to our prediction, sensitivity to the presence of gaps in tactile stimulation of the right forearm was not reduced when participants made asymmetrical movements during mirror visual feedback, as compared to when they made symmetrical or asymmetrical movements with no visual feedback. Instead, sensitivity was reduced when participants made symmetrical movements during mirror visual feedback relative to the other three conditions. We suggest that small discrepancies between sensory and motor information, as they occur during mirror visual feedback with symmetrical movements, can impair tactile processing. In contrast, asymmetrical movements with mirror visual feedback may not impact tactile processing because the larger discrepancies between sensory and motor information may prevent the integration of these sources of information. These results contrast with previous reports of anomalous sensations during exposure to both low and high sensorimotor conflict, but are nevertheless in agreement with a forward model interpretation of perceptual modulations during goal directed movement

Altered updating of bodily and spatial representations after tool-use in complex regional pain syndrome

Distorted representations of the body and peripersonal space are common in complex regional pain syndrome (CRPS), and might modulate its symptoms (eg, asymmetric limb temperature). In pain-free people, such representations are malleable, and update when we interact with objects in our environment (eg, during tool-use). Distortions are also common after immobilisation, but quickly normalise once movement is regained. We tested the hypothesis that people with CRPS have problems updating bodily and spatial representations, which contributes to the maintenance of their distorted representations by preventing normalization. We also explored spatially defined modulations of hand temperature asymmetries, and any influence of updating bodily and spatial representations on this effect. Thirty-six people with unilateral CRPS (18 upper limb and 18 lower limb) and 36 pain-free controls completed tool-use tasks considered to alter body and peripersonal space representations (measured using tactile distance judgements and a visuotactile crossmodal congruency task, respectively). We also tested how the arrangement (crossed and uncrossed) of the hands and tools affected hand temperature. In upper-limb CRPS, the nonaffected arm representation updated normally, but the affected arm representation updated in the opposite to normal direction. A similar pattern was seen in lower-limb CRPS, although not significant. Furthermore, people with CRPS showed more pronounced updating of peripersonal space than the controls. We did not observe any modulation of hand temperature asymmetries by the arrangement of hands or tools. Our findings show enhanced malleability of bodily and spatial representations in CRPS, which may suggest that central mechanisms are altered in this condition.</p