how does a spinal cord injury affect the brain

How does a spinal cord injury affect the brain despite occurring below the level of the head, creating a complex neurological relationship that extends beyond mobility limitations. Although many people associate spinal cord injuries primarily with loss of movement and sensation, these injuries disrupt vital communication pathways between the brain and other parts of the body. This disruption consequently impacts cognitive function and can lead to significant neurological changes.

The effects of spinal cord injury on brain function are frequently overlooked. Research shows that individuals with spinal cord injuries may experience impairments in memory, attention span, problem-solving abilities, and communication skills. Additionally, studies have documented spatial memory impairment and depressive-like behavior following spinal cord trauma. These brain and spinal cord injury complications can manifest during the acute phase immediately after injury and potentially persist as long-term challenges.

This article explores the multifaceted relationship between spinal cord injuries and brain function, examining how damage to the spinal cord can trigger neuroinflammation, cognitive deficits, and emotional changes. Understanding these connections provides valuable insights for both patients and healthcare providers navigating the comprehensive impacts of spinal cord trauma.

Disruption of Brain-Body Communication After SCI

Spinal cord injury fundamentally severs the intricate neural communication networks between the brain and body. This disruption affects not only movement but also transforms how the brain processes information and adapts to reduced input.

Loss of Afferent and Efferent Signaling Pathways

Traumatic SCI results in abrupt silencing of communication between neural circuits caudal and rostral to the injury site. This disconnection affects two critical neural highways: afferent pathways carrying sensory information from peripheral receptors to the central nervous system, and efferent pathways transmitting motor commands from the brain to muscles and glands. The dorsal columns, which contain sensory axons conducting afferent inputs from various receptors, are especially vulnerable to injury due to their location in the spinal cord. In upper motor neuron syndrome (UMNS), the brain-spinal cord network becomes a bottleneck, with total information rate approaching zero. Similarly, in lower motor neuron syndrome (LMNS), the total rate approaches zero with the loss of spinal cord motoneurons.

Impact on Sensory Feedback and Motor Control

Following SCI, the spinal network experiences dramatically altered input dynamics. Without supraspinal control, sensory inputs exert outsized influence on the spinal cord below the injury. This imbalance leads to disinhibition of spinal reflexes, hyperreflexia, and motoneuron hyperexcitability. Furthermore, the loss of afferent signaling severely impacts the brain’s ability to receive accurate sensory feedback, creating difficulties in motor control.

Proprioceptive feedback, which transmits information about ongoing motor system states, becomes particularly crucial after injury. Studies show mice lacking muscle spindle feedback circuits fail to display the activity-dependent reorganization needed for recovery after SCI. Moreover, electrophysiological assessments in humans with SCI reveal that peripheral nerve stimulation affects corticospinal excitability differently than in uninjured individuals.

Altered Brain Plasticity Due to Reduced Input

The brain demonstrates remarkable adaptability following SCI through cortical reorganization. After injury, the functional “silence” in corresponding representative areas of the sensorimotor cortex triggers neuronal circuit remodeling. This reorganization occurs through several mechanisms: dendritic spine density changes in different cortical layers, BDNF upregulation, and homeostatic regulation where cortical neurons modify their synaptic strength and intrinsic properties.

In non-human primates, lesions of the dorsal columns at the cervical spinal cord level prompt large-scale reorganization in multiple cortical areas, including primary motor cortex and somatosensory cortex. Studies using functional magnetic resonance imaging have shown that electrical stimulation of the forelimb after thoracic SCI elicits responses in deafferented hindlimb S1 and expansion of forelimb S1. Essentially, the brain attempts to compensate for lost connections through functional and structural modifications, though these changes can either facilitate recovery or lead to maladaptive outcomes.

Neuroinflammation and Microglial Activation in the Brain

Neuroinflammation emerges as a critical secondary consequence of spinal cord injury (SCI), extending well beyond the injury site to affect brain regions through systemic inflammatory processes. This brain-specific inflammatory response involves complex cellular mechanisms that contribute to cognitive and emotional changes after injury.

M1-Type Microglia in Hippocampus and Cortex

Within minutes after SCI, microglia in the central nervous system transform into an inflammation-related state, initiating critical inflammatory cascades. These resident immune cells polarize into two distinct phenotypes: classically activated (M1) and alternatively activated (M2) microglia. The M1 phenotype predominates in brain regions like the hippocampus and cortex following injury. Studies examining SCI-induced cognitive decline found significant upregulation of M1-type microglial markers in the hippocampus, including TNFα, iNOS, CD86, CCL2, CCL3, and IL6. Notably, these changes persist for extended periods, with some markers increasing as late as 12 weeks post-injury. Subsequently, M1 microglia contribute to prolonged inflammation that damages surrounding neural tissue through multiple neurotoxic mechanisms.

Increased IL-6 and TNFα Expression Post-SCI

The spinal cord rapidly increases production of pro-inflammatory cytokines within hours of injury, which then spread systemically. Indeed, TNFα, IL-1β, and IL-6 protein levels rise significantly 3 hours after injury, with some returning toward baseline by 24 hours. Nevertheless, certain inflammatory markers remain elevated long-term, with studies showing TNFα and IL-6 mRNA levels sustained in the brain 14 days after injury. This prolonged inflammatory response affects neuronal health, as microglia secreting these cytokines promote neurodegeneration. In vitro experiments demonstrate that activated microglia release CXCL2, IL-6, and TNFα when stimulated by circulating extracellular vesicles from SCI animals. These inflammatory factors ultimately lead to neuronal apoptosis, with studies showing increased cleaved caspase-3 expression in neurons exposed to inflammatory mediators.

MHC II Upregulation in Activated Microglia

Major histocompatibility complex class II (MHC II) expression significantly increases in microglia following SCI, serving as a hallmark of their activation state. While MHC II expression is low in healthy brain tissue, it becomes heavily upregulated on microglia after inflammatory processes. In SCI models, MHC II immunoreactivity increases significantly in the hippocampus, particularly in cells displaying activated microglial morphology. Within the brain, this upregulation follows a temporal pattern, with MHC II-positive microglia appearing first in gray matter during acute phases (4-14 days) and later shifting to white matter during subacute phases (1-4 months). The increased MHC II expression enables microglial interaction with other immune cells, potentially exacerbating neuroinflammatory responses that impact cognitive function after SCI.

Cognitive and Emotional Impairments Linked to SCI

Cognitive and emotional changes represent measurable outcomes of brain dysfunction following spinal cord injury. These deficits have been documented through various behavioral tests designed to assess specific aspects of cognitive function and emotional regulation.

Spatial Memory Deficits in Morris Water Maze

The Morris Water Maze (MWM) test reveals significant spatial learning and memory impairments in SCI animal models. Studies demonstrate that SCI mice spend substantially less time in the target quadrant compared to sham-operated controls during probe tests. Specifically, injured animals show poorer performance by training day 4, with significant differences detected between sham and injured groups. Beyond increased latency times, SCI causes animals to rely primarily on looping search strategies rather than spatial strategies, indicating fundamental changes in spatial problem-solving. These deficits extend beyond mere motor impairments, as confirmed through careful swim strategy analyzes.

Depression-like Behavior in Tail Suspension Test

Approximately 22% of people with SCI develop major depressive disorder—nearly three times higher than the general population rate of 8.1%. In rodent models, the tail suspension test reveals significant depression-like behavior. SCI mice exhibit markedly increased immobility time compared to control animals, reflecting behavioral despair. Correspondingly, the sucrose preference test shows reduced sweet water consumption without changes in regular food intake. These behaviors emerge in roughly one-third of rats with SCI, closely matching clinical populations.

Reduced Novel Object Recognition Performance

Recognition memory, which relies less on locomotion abilities, shows significant impairment following SCI. In novel object recognition tests, injured animals spend less time exploring novel objects compared to familiar ones. These deficits indicate impaired ability to discriminate between novel and familiar stimuli. Importantly, this type of memory depends on medial temporal lobe and perirhinal cortex function, with certain roles for hippocampal and prefrontal regions.

Working Memory Impairment in Y-Maze Test

Working memory deficits appear consistently in SCI models. The Y-maze spontaneous alternation test reveals significant reduction in alternation behavior following SCI. This reduction indicates dysfunctional spatial working memory. Unlike other tests, Y-maze performance is minimally affected by motor deficits, making it particularly valuable for SCI research. Therefore, these findings confirm genuine cognitive impairment rather than testing artifacts due to mobility limitations.

Cell Cycle Activation and Neurodegeneration

Beyond inflammation, spinal cord injury triggers abnormal cell cycle activation in post-mitotic neurons, initiating molecular cascades that lead to neurodegeneration.

Cyclin D1 and CDK4 Expression in Hippocampus

Following SCI, multiple cell cycle-related genes become upregulated in the hippocampus, including cyclins A1, A2, D1, and proliferating cell nuclear antigen (PCNA). The E2F1 transcription factor shows rapid elevation at 24 hours after injury, whereas other cyclins increase significantly at 10 weeks post-injury. Immunohistochemistry reveals numerous cyclin D1-positive cells in both hippocampus and cerebral cortex, primarily co-localizing with NeuN+ neurons rather than with microglia or astrocytes. This aberrant expression drives neurons toward apoptosis instead of division, as terminally differentiated neurons cannot complete the cell cycle.

Neuronal Loss in CA1 and Dentate Gyrus

Initially, no differences in neuron counts appear at 7-8 days post-SCI. However, by 10-12 weeks, significant neuronal loss occurs in multiple hippocampal regions. TUNEL assays confirm that apoptotic cells increase dramatically in both CA1 and dentate gyrus regions of injured animals. This delayed neurodegeneration results from abnormal cell cycle re-entry, as neurons lack mechanisms to complete division safely.

Reduced Neurogenesis: DCX+ Cell Decline

Adult neurogenesis becomes significantly impaired after SCI. The number of doublecortin (DCX+) cells, which mark immature neurons, decreases in the subgranular zone during both acute (7 days) and chronic (50 days) phases post-injury. Additionally, BrdU labeling shows reduced incorporation of new neurons (NeuN+/BrdU+) into the granule cell layer. This neurogenesis reduction occurs through decreased proliferation and increased death of amplifying neural progenitors (ANPs).

CR8 Inhibitor Effects on Brain Recovery

The selective cyclin-dependent kinase inhibitor CR8 produces remarkable neuroprotective effects when administered systemically after SCI. CR8 significantly suppresses cell cycle gene expression, reduces microglial activation, and prevents neurodegeneration in the brain. Importantly, CR8 treatment increases the number of surviving neurons in CA1 and dentate gyrus regions. It also reverses the decline in DCX+ neurons in the dentate gyrus, effectively protecting against SCI-induced cognitive impairments by interrupting aberrant cell cycle activation.

Conclusion

Spinal cord injuries clearly extend far beyond the physical limitations most commonly associated with them. Research demonstrates that disruption of neural communication pathways between brain and body triggers cascading effects throughout the central nervous system. Consequently, patients experience not only motor deficits but also significant cognitive and emotional changes due to altered brain function.

Neuroinflammation emerges as a critical mechanism linking spinal trauma to brain dysfunction. The activation of M1-type microglia in brain regions like the hippocampus and cortex, along with increased expression of pro-inflammatory cytokines, creates a neurotoxic environment that persists long after the initial injury. This inflammatory response ultimately contributes to measurable cognitive deficits, particularly affecting spatial memory, working memory, and emotional regulation.

Additionally, the abnormal activation of cell cycle proteins in post-mitotic neurons represents another pathway through which spinal injuries compromise brain health. Neurons forced into cell cycle re-entry face inevitable death rather than division, explaining the delayed neurodegeneration observed in hippocampal regions. The resulting loss of neurons in crucial brain areas therefore explains many cognitive symptoms experienced by SCI patients.

Understanding these brain-specific consequences of spinal cord injury holds significant clinical implications. Treatment approaches must address not only physical rehabilitation but also cognitive and emotional health. Promising research with cell cycle inhibitors such as CR8 demonstrates potential neuroprotective effects that may prevent brain deterioration after spinal trauma.

The relationship between spinal cord injury and brain function thus represents a complex bidirectional interaction rather than isolated systems. Future therapeutic strategies should target both spinal and cerebral pathology to achieve optimal recovery and quality of life for patients with spinal cord injuries.