Spinal Cord Stimulation Enabling Movement in Humans with Spinal Cord Injury

Post by Amanda McFarlan

What's the science?

Epidural electrical stimulation is a therapeutic treatment for individuals with spinal cord injuries that involves applying continuous electrical current to the lower part of the spinal cord. This technique has been shown to restore movement in animal models of spinal cord injury, but has been less effective in treating humans. It is hypothesized that action potentials induced by epidural electrical stimulation may collide with naturally-occurring action potentials conveying proprioceptive information (information about where one’s body is in space), disrupting the flow of information traveling to the brain. This may be a larger issue for humans compared to smaller mammals. This week in Nature Neuroscience, Formento and colleagues investigated why treatment of spinal cord injury with epidural electrical stimulation is less effective in humans compared to other mammals.

How did they do it?

The authors tested whether epidural electrical stimulation produces action potentials that travel in the opposite direction (i.e. towards the periphery, away from the brain) from that of sensory afferents (nerve fibers). To do this, they inserted subcutaneous needle electrodes in 2 patients with chronic spinal cord injury and recorded from their sural nerve, the proximal and distal branches of their tibial nerve, and their soleus muscle while applying epidural electrical stimulation. They also developed a computational model of proprioceptive afferents in rats and in humans to determine the probability of having a collision between naturally occurring action potentials and action potentials induced by epidural electrical stimulation. Next, they aimed to determine whether epidural electrical stimulation disrupts proprioception in humans. They had 2 participants with spinal cord injuries sit in a robotic system that passively moved their leg and asked the participants to indicate the direction of movement of their leg as they perceived it (measuring proprioception). They performed this experiment with and without epidural electrical stimulation. In subsequent experiments, they developed computational models to investigate the underlying mechanisms responsible for the disruption of proprioception in humans treated with epidural electrical stimulation. They used these models to investigate the impact of epidural electrical stimulation on proprioceptive feedback circuits during movement in rats and humans. Lastly, they examined how targeting a smaller pool of afferents with high-frequency, low amplitude bursts (rather than targeting all sensory afferents with continuous electrical stimulation) may resolve the issue of disrupted proprioception.

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What did they find?

The authors found that epidural electrical stimulation elicited responses in the proximal and distal branches of the tibial nerve as well as the sural nerve. These responses occurred before motor responses in the soleus muscle, suggesting that these action potentials were traveling in the opposite direction of sensory afferents (i.e. towards the periphery). Using a computational model, the authors determined that the probability of having a collision between a naturally occurring action potential and an action potential induced by epidural electrical stimulation was much higher in humans compared to rats. They determined that patients were able to correctly identify the direction of movement 100% of the time in the absence of epidural electrical stimulation. In contrast, when electrical stimulation was delivered at 1.5 times stronger than the muscle response threshold, patients were not able to identify the direction of movement as they lacked awareness of their leg position and motion. These findings suggest that action potentials traveling in the opposite direction of naturally occurring action potentials in sensory afferents may be responsible for blocking proprioceptive information from reaching the brain in humans, but not rats. Furthermore, when assessing proprioceptive feedback circuits during movement, the authors showed that epidural electrical stimulation blocked proprioception in humans, but not rats, and that this interfered with the recruitment of alternating antagonist motor neurons required to produce movement. Finally, a computational model revealed that high-frequency bursts of epidural electrical stimulation targeting smaller population of sensory afferents greatly reduced the amount of proprioceptive information that was blocked with continuous electrical stimulation. These findings suggest that a high-frequency, low-amplitude stimulation protocol may be key for treating human patients with spinal cord injuries with epidural electrical stimulation. Note: In a companion study published in Nature at the same time, the authors implemented their spatially selective stimulation approach in spinal cord injury patients and found it to be beneficial. 

What's the impact?

This is the first study to show that treatment with continuous epidural electrical stimulation is less efficient in humans compared to other small mammals because it disrupts proprioception. Further studies focused on improving electrical stimulation protocols will provide insight into how proprioception can be better preserved to make this technique useful for treating humans with spinal cord injuries. Improving this technique could be instrumental in helping individuals suffering from spinal cord injuries regain mobility.   

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Formento et al. Electrical spinal cord stimulation must preserve proprioception to enable locomotion in humans with spinal cord injury. Nature Neuroscience (2018). Access to the original scientific publication here.

Nested Theta Sequences Contribute to Formation of Long-Term Spatial Memory

Post by Kayla Simanek

What's the science?

Spatial exploration causes the sequential activation of specific neurons in the hippocampus (i.e. 'place cells') to track the ongoing location of the animal. The same neuronal sequences of activity are replayed at a faster rate during sleep for long-term memory commitment. How are these sequences initially memorized during exploration so that they can be replayed during sleep? Sequences are formed at two different time scales: a fast (theta) time scale and a slow, behavioral time scale. Theta sequences are ‘nested’ within slow behavioral sequences. The role of these different time scales in initial spatial memory formation during wakefulness had remained untested until now. This week in Science, Drieu and colleagues investigate whether theta sequences contribute to the initial formation of spatial memories.

How did they do it?

The authors put rats on a moving model train in a novel environment to test their ability to form long-term spatial memories. A treadmill on the model train was either turned off (passive travel) to disrupt theta sequences or turned on (active travel) to leave them intact. Active travel generates intact nested theta sequences while passive transportation is known to disrupt the precise timing of sequential place cell activation. Therefore, passive travel was expected to cause theta sequences to break-down in this study. Rats were tested in three sessions: passively, then actively, and passively again, alternated with periods of sleep, to determine if nested theta sequences were required for accurate replay of spatial memories during periods of sleep. The authors used a Bayesian reconstruction model to statistically analyze time scale patterns. Two quantifications were used: a combined value for trajectory score and slope to assess the quality of memory reconstruction, and a quadrant score to assess the direction of the reconstituted trajectory. To determine if neural sequences formed during initial spatial memorization were committed to long-term memory during sleep, the authors compared sleep sequences to those formed during wakefulness. Additionally, the sleep patterns of pre-active and post-active sessions were compared to confirm that sleep patterns observed were indeed reflective of those patterns formed during wakefulness and not from unrelated, pre-existing connectivity.

What did they find?

As hypothesized, the authors found that slow time scales were identical in all sessions and that genuine theta sequences were present only in active travel sessions. Active travel produced higher valued pairs of slopes and trajectory scores, consistent with greater quadrant scores, compared to passive travel, which confirmed that theta sequences were degraded in passive travel sessions and not active sessions. Neural sequences were found to be intact in sleep sessions after active travel (when theta sequences were previously formed in wakefulness) but not passive travel. This indicates a failure to commit short-term spatial memory to long-term after passive travel. Interestingly, theta sequences were perturbed to a lesser degree in the sleep session that followed the second round of passive travel compared to the first. This rules out the possibility that the emergence of theta sequences during active travel merely resulted from repeated experience. Finally, it shows that previously consolidated memory from active behavior can be undone by perturbation of theta sequences during passive travel.

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What's the impact?

This study is the first to show that nested theta sequences are essential to store initial memory traces which are later consolidated during sleep. Ultimately, this study sheds light on the conversion of short-term spatial memory to long-term memory. These findings advance our understanding of spatial memory consolidation and may have implications for other types of memory consolidation.

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Drieu et al. Nested sequences of hippocampal assemblies during behavior support subsequent sleep replay. Neuroscience (2018). Access the original scientific paper here.

Abnormal Organization of Brain Networks Predicts Psychosis in At-Risk Youth

Post by Shireen Parimoo

What's the science?

Schizophrenia is a psychiatric disorder that manifests when a psychotic episode occurs, typically in adolescence and young adulthood when the brain is still developing. A prodromal stage of schizophrenia usually occurs prior to the onset of a psychotic episode, where cognitive function or changes in behaviour occur. Previous studies have found that the brain networks are organized differently in individuals with schizophrenia, however it is not known if organization of functional brain networks during the prodromal stage is related to the occurrence of a psychotic episode. This week in Molecular Psychiatry, Collin and colleagues used functional magnetic resonance imaging (fMRI) and graph theory to investigate the organization of brain networks in individuals who were at risk of developing psychosis.

How did they do it?

Participants included 158 adolescents and young adults who were deemed to be at-risk for developing psychosis through the Shanghai At Risk for Psychosis program. They were matched to 93 healthy participants of the same age, sex, and education level. The participants’ brain activity was recorded in an fMRI session at the beginning of the study. Their at-risk status was determined at two time points (roughly a year apart) using the Structured Interview for Prodromal Symptoms, which provides a measure of whether participants are in the prodromal stage. By the second interview, 23 participants had developed psychosis. The authors used graph theory to create functional connectomes of brain networks. Brain regions are said to be functionally connected when their activity is correlated, and a group of functionally connected regions represents a functional network. Functional connectomes were constructed for each participant as well as for each group of participants: these were healthy participants, at-risk participants, and at-risk participants who later developed psychosis. Functional connectomes of those at-risk and at-risk who later developed psychosis were compared to that of the healthy group, which allowed the authors to examine if brain networks are organized differently between groups.

What did they find?

The authors found that functional networks across all groups were organized into five modules consisting of the central-executive, sensorimotor, visual, paralimbic, and default-mode networks, each with different functional roles. An additional cingulo-opercular network was identified in at-risk individuals who later developed psychosis, but not in healthy or at-risk individuals. The functional connectomes of the healthy and at-risk individuals were more similar to each other than to to participants at-risk who later developed psychosis. Moreover, several brain regions that are affected early in schizophrenia were found to be part of different functional networks in the different participant groups. For example, the superior temporal gyrus was part of the sensorimotor network in healthy and at-risk individuals, but this brain region was functionally connected to regions of the paralimbic network in individuals who went on to develop psychosis. Thus, functional networks were organized differently in individuals who later developed psychosis, and this abnormal organization was associated with a three-fold risk of developing psychosis.

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What's the impact?

This study found that at-risk adolescents and young adults who exhibit abnormal organization of brain networks early on eventually develop psychosis, whereas at-risk youth with similar functional networks and healthy individuals do not. This novel insight into the predictive value of brain network organization for the onset of psychosis can be used to identify at-risk individuals and potentially establish preventative measures to mitigate the occurrence and severity of psychosis.

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Dr. Collin would like to acknowledge support of a Marie Curie Global Fellowship.

Collin et al. Functional connectome organization predicts conversion to psychosis in clinical high-risk youth from the SHARP program. Molecular Psychiatry (2018). Access the original scientific publication here.