Innovations In Clinical Neuroscience

MAR-APR 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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H O T T O P I C S I N N E U R O S C I E N C E 45 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 patients with TBI. Tricyclic antidepressants reportedly have less efficacy in relieving symptoms of post-TBI depression when compared to non-TBI depression and induce more unfavorable side effects. Prescribing the norepinephrine-dopamine reuptake inhibitor, bupropion, remains controversial because this medication decreases seizure thresholds; yet, a multicenter study did not reveal an increase in ictal events while utilizing this medication in patients following TBI. Despite pharmacotherapies for TBI-induced depression having been described, 8 more research is needed to identify those with the best efficacy. ELECTROCONVULSIVE THERAPY Electroconvulsive therapy (ECT) is a powerful tool in the treatment of mood and psychotic disorders. It requires a short-term general anesthesia and paralysis prior to administering brief current pulses that induce a therapeutic convulsion. 18 Patients usually receive 6 to 12 treatments for full therapeutic benefit; 18,19 but the number of ECT applications is titrated individually for each case. The precise mechanism underlying the efficacy of ECT remains unclear, but one theory is that it promotes neuroplasticity by optimizing or "resetting" existing brain networks. 20 Functional magnetic resonance imaging (MRI) research reveals symptom resolution correlating with changes in corticolimbic circuits following ECT; this supports the hypothesis of ECT-mediated neuroprotection and plasticity. 21 Similarly, certain functional brain networks are disrupted in patients with depression and normalize in those who experience a therapeutic response to ECT. 22 ECT also induces neurogenesis and a release of trophic factors. An increase in the thickness of the gray matter of the cerebral cortex is documented in subjects with depression who have undergone ECT. 23 Animal studies have demonstrated neurogenesis in response to ECT in frontal limbic circuitry 24 and the hippocampus 25 and increases in expression of brain-derived neurotrophic factor 26 and vascular endothelial growth factor. 27 ECT also produces genetic and epigenetic changes. 28 Current hypotheses regarding the mechanism of ECT 's actions in mood disorders include beneficial effects on various cellular and biochemical pathways. 29 However, it is notable that these proposed mechanisms of action have been based on studies limited to TBI-naïve animals and humans. ECT FOR POST-TBI DEPRESSION Since patients following a TBI have a reduced seizure threshold and a greater risk for developing post-traumatic epilepsy, there is some reluctance to apply ECT, 14 especially since it seems counterintuitive to induce convulsions for therapeutic advantage. 30 The stigma associated with ECT also diminishes the frequency of its application. There is a dearth of information about the use of ECT in people with depression following TBI. There are no published investigations that demonstrate adverse effects of ECT in patients who are post-TBI; only three case reports document ECT use following a TBI, and each one describes amelioration of mood symptoms and neurocognitive improvement after ECT. 31–33 A 28-year-old man with TBI developed medication-resistant depression but experienced a good response to ECT. 31 He received it again for a relapse years later. At that time, neuropsychological testing documented that his cognitive performance did not deteriorate and even improved following ECT treatment. Similar clinical efficacy was evident following ECT treatment of depression in two individuals with gunshot-inflicted brain trauma. 32,33 These three clinical vignettes constitute the bulk of the current literature regarding ECT in treating patients with unipolar depression following a TBI. See Table 1 for a summary of the clinical circumstances in each case. All three patients were diagnosed with major depression prior to their TBI, but mood symptoms significantly worsened after their injuries. Rates of post-TBI depression are higher in patients with a premorbid psychiatric history of an affective disorder. 7–12 However, those without depression prior to TBI still experience an increased risk of developing a post-TBI mood disorder during the first year following their brain injury. 11 There are no reports on ECT as treatment for new cases of depression following TBI. There are reports of ECT's positive effects when used in patients with other organic neurological disorders, such as tumors or hydrocephalus, and these reports are sometimes referenced in support of ECT in the TBI population; however, such disorders are pathophysiologically distinct from TBI. 32 There is little data suggesting harm from utilizing ECT to treat persons with post-TBI mood disorders. CONCLUSION TBI is a distinct and complex pathophysiological entity. Neurocognitive deficits and mood disorders are common sequelae of TBI. While nonmodifiable factors influence risk of developing post- TBI depression, there is also evidence that biological factors are involved. People who have suffered TBI are at increased risk for ictal events and cognitive impairment. ECT has been documented to successfully treat patients with post-TBI mood symptoms in only three published cases. While these vignettes suggest that ECT might be a safe and effective therapeutic option in treating individuals with post-TBI depression, more research is needed to establish its safety and beneficial clinical outcomes among this patient population. REFERENCES 1. Dmirtas-Tatlidede A, Vahabzadeh-Hagh AM, Bernabeu M, et al. Noninvasive brain stimulation in traumatic brain injury. J Head Trauma Rehabil. 2012;27(4):274. 2. Von Baumgarten L, Trabold R, Thal S, et al. Role of cortical spreading depressions for secondary brain damage after traumatic brain injury in mice. J Cereb Blood Flow Metab. 2008;28(7):1353–1360. 3. Licastro F, Hrelia S, Porcellini E, et al. Peripheral inflammatory markers and antioxidant response during the post-acute and chronic phase after severe traumatic brain injury. Front Neurol. 2016. 7:189. 4. Wang KK, Yang Z, Yue JK, et al. Plasma anti-glial fibrillary acidic protein autoantibody levels during the acute and chronic phases of traumatic brain injury: a transforming research and clinical knowledge in traumatic brain injury pilot study. J Neurotrauma. 2016;33(13):1270–1277. 5. Tsuda S, Hou J, Nelson RL, et al. Prolonged

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