Shared Functional Neuroimaging Abnormalities In Depression And Epilepsy

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Utilizing various imaging techniques, functional abnormalities in both epilepsy and depression have been identified in common subcortical structures, as well as similar regions of the frontal and temporal lobes.

Frontal lobe involvement in primary depression has been demonstrated with functional neuroimaging and neuropsychological studies (Baxter et al., 1989). Frontal lobe associated executive dysfunction has been consistently shown in studies on depressive illness. Abnormalities on neuropsychological testing have been correlated to reduced blood flow in the mesial prefrontal cortex (Bench )t al. ) 1993 ) Dolan et al., 1994).

Frontal lobe mediated executive dysfunction has also been recognized in TLE (Hermann et al., 1988) Horner et al., 1996) Martin et al., 2000), prominently among patients with comorbid depression, correlating with bilateral inferior frontal hypometabolism by 18F-flourodeoxyglucose positron emission tomography (FDG-PET) (Bromfield et al., 1992 ) Jokeit )t al., 1997) . In a study by Victoroff et al. (1994) of 53 patients with epilepsy, evaluated by FDG-PET and psychiatric interview, severity of temporal hypometabolism was also found to have significant correlation with a history of MDD, more frequently with left temporal lateralization (Victoroff et al., 1994).

Gilliam )t al. performed a pilot study of the association between depressive symptoms, clinical variables, and FDG-PET in 62 consecutive patients with refractory localization-related epilepsy. Age, seizure rate, number of current medications, and scores on the adverse events profile were similar between 55 patients with an abnormal PET compared to the 7 patients with a normal PET. BDI scores were, in contrast, significantly higher in the group of patients with an abnormal PET scan, the majority of which showed abnormalities in the temporal lobes (Gilliam et al., 2004a).

Using (99 m)Tc-HMPAO single-photon emission-computed tomography (SPECT) in a study of 31 patients with localization-related epilepsy, higher scores on the BDI were associated with decreased contralateral temporal and bilateral frontal perfusion in patients with left hemispheric epilepsy (Schmitz et al., 1997).

As discussed previously, deficits in serotonin may predispose to the development of major depression. Activation of 5-HT1A receptors located on serotonin cell bodies in the midbrain dorsal raphe nucleus inhibits the firing of serotonergic neurons and diminishes the release of 5-HT in the prefrontal cortex. As reviewed by Kanner, decreased serotonergic innervation in terminal tissues has been suggested by studies of brain, plasma, and platelets of depressed patients (Kanner, 2005).

Studies have identified serotonergic dysfunction in the ventral prefrontal cortex to be associated with patients with suicidal behavior (Oquendo et al., 2003) . A lower density of 5-HT1A receptors in the hippocampus and a lower affinity of 5-HT1 binding sites in the amygdala have been observed in pathologic specimens of untreated depressed patients who committed suicide (Cheetham )t al. ) 1990). The binding of the radiolabel [3H]8-hydroxy-2-(di-«-propyl)aminotetralin ([3H]8-OH-DPAT), an agonist at inhibitory 5-HT1A autoreceptors, was excessively increased in the midbrain dorsal raphe nuclei of suicide victims with MDD in comparison with normal controls, offering further evidence of diminished activity of serotonergic neurons (Stockmeier et al., 1998).

Using the 5-HT1A receptor antagonist [Carbonyl-11C]WAY-100635, a PET study of 25 medicated and medically untreated patients with depression revealed decreased serotonergic binding potential in the frontal, temporal, and limbic cortex as compared to healthy controls (Sargent ;t al., 2000; . Another PET investigation using [Carbonyl-11C]WAY-100635, similarly measured decreased 5-HT1A binding in the mesial temporal cortex and the raphe nuclei in 12 patients with familial recurrent major depressive episodes when compared to controls (Drevets et al.; 1999).

The decreased availability of 5-HT1A receptors may reflect receptor loss, decreased expression of receptors, altered receptor function, decreased receptor affinity, or at least theoretically, increased receptor occupancy. Downregulation of autoreceptors in the raphe may result from reciprocal inter-connections from regions of impaired serotonergic transmission in the amygdala, hippocampus, insular and cingulate cortex. In the case of epileptic patients with associated structural abnormalities, such as hippocampal sclerosis, associated neuronal loss may contribute to a low 5-HT1A receptor binding potential. Potentially, downregulation of postsynaptic 5-HT1A receptors may occur as a result of repetitive seizures (Savic et al.; 2004).

A PET study of serotonergic activity using [Carbonyl-11C]WAY-100635 by Savic et al. (2004) demonstrated significantly reduced 5-HT1A receptor binding potential in the hippocampus, amygdala, anterior cingulate, and lateral temporal neocortex ipsilateral to the seizure focus, as well as the insula, midbrain raphe nuclei, and to a lesser extent, the contralateral hippocampus of 14 patients with TLE. Six of the 14 patients met criteria for the interictal dysphoric syndrome. However, of these structures, only the anterior cingulate region was significantly correlated with depression rating scores. The study was not powered to detect small potential associations. As extratemporal limbic changes were observed only ipsilaterally to the side of seizure activity, the authors favored the hypothesis that they were related to the epileptogenic process rather than being secondary to the depressive state. They further hypothesized that the interictal affective disorder in mesial TLE may result from an increased vulnerability due to impaired serotoner-gic transmission in limbic structures of the seizure-generating hemisphere.

Another group, using the radioligand [18F]tra«s-4-fluoro-N-2-[4-(2-methoxy-phenyl)piperazin-1-yl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide or ([18F] FC-WAY), a selective 5-HT1A receptor antagonist, also found lower serotonergic binding in patients with TLE ipsilateral to the epileptic focus in the inferior medial and lateral temporal regions, insula, and raphe by PET. After partial volume correction, decreased serotonergic activity in the mesial, but not lateral temporal structures and insula remained highly significant. A significant inverse relationship between BDI scores and 5-HT1A binding potential in the hippocampus ipsilateral to the seizure focus was reported (Giovacchini et al.; 2005; . Differences between the results of the studies may have been accounted for in part by partial volume effects, patient sample sizes, the use of different radioligands, and variations in analytic methods.

Theodore et al. (2007) conducted a similar PET study using the radioligand [18F]FCWAY. Depressive symptoms measured with the BDI were examined in relation to 5-HT1A receptor binding as assessed by PET, MTS on MRI, and epileptic focus laterality in 45 patients with TLE. Corrected for partial volume effects, 5-HT1A binding was significantly lower in the hippocampus ipsilateral to the epileptic focus, however bilateral hippocampal reductions were also significantly present. Again, there was a significant inverse relation between ipsilateral 5-HT1A binding potential and the BDI. Side of focus, the presence of MTS, and patient gender did not affect the BDI significantly.

Using 4,2-(methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]ethylpi-perazine (18F-MPPF), a different 5-HT1A tracer, investigators were able to demonstrate that a decrease in binding potential of 5-HT1A in patients with TLE was significantly more prominent in regions of seizure onset and propagation, as defined by intracranial recordings with stereoelectroencephalography (SEEG). Again, 5-HT1A binding remained decreased even in the setting of a normal quantitative and qualitative MRI (Merlet et al., 2004).

Of interest, in a PET study of 11 patients with juvenile myoclonic epilepsy, using [Carbonyl-11C]WAY-100635, a decreased serotonergic binding potential was also observed in the dorsolateral prefrontal cortex, raphe nuclei, and hippocampi when compared to 11 control subjects (Meschaks et al., 2005).

In a recent 1H magnetic resonance spectroscopy (1H-MRSI) study of 31 patients with TLE, Gilliam et al. (2007) found a significant correlation of severity of depression symptoms with the extent of voxels containing an abnormal hippocampal Cr/NAA metabolite ratio. All subjects had at least one complex partial or generalized tonic—clonic seizure within the last 3 months, and all patients were on at least one antiepileptic medication. Linear regression analysis confirmed an independent association of 1H-MRSI abnormalities with the depression scale of the Profile of Mood States (POMS), and the absence of association with other measured seizure or self-perceived disability variables. Overall, the model explained 57% of the variance in depressive symptoms. The study is unique in demonstrating the degree of depression correlating with spatial involvement of a biomarker of neuronal dysfunction within the limbic region. Given the association of areas of decreased NAA concentration with cerebral regions of interictal spiking and seizure onset (Garcia et al., 1997 ; Shih et al., 2004) , the authors proposed that depression symptoms in TLE may be due to hyperexcitable neurons in the limbic network (Figures 6.2 and 6.3).

Aberrancies in NAA levels and glucose uptake may represent differing mechanisms of cellular metabolic dysfunction. While glucose metabolism may be more dependent on pyramidal cell activation and regional neuron/glia ratios, NAA synthesis is dependent on mitochondrial enzymes, which may be potentially more sensitive to hippocampal functional disruption. A comparison of ^-MRSI with FDG-PET in TLE, demonstrated that hippocampal Cr/NAA measures did not correlate with glucose metabolism (Knowlton et al.; 2002). These differences may

Hippocampus Tra Mri

FIGURE 6.2 An example of a 1H-MRSI ratio map in a patient with mesial TLE. The map of the region of abnormality was determined by inclusion of all voxels within the hippocampi that had an abnormal creatine/N-acetylaspartate (Cr/NAA) ratio defined as more than two standard deviations beyond normal. The degree of elevation of Cr/NAA is color coded and corresponds to the abnormal ratios; values of 0.9—1.6 by increments of 0.1. Source: Gilliam et al. (2007).

FIGURE 6.2 An example of a 1H-MRSI ratio map in a patient with mesial TLE. The map of the region of abnormality was determined by inclusion of all voxels within the hippocampi that had an abnormal creatine/N-acetylaspartate (Cr/NAA) ratio defined as more than two standard deviations beyond normal. The degree of elevation of Cr/NAA is color coded and corresponds to the abnormal ratios; values of 0.9—1.6 by increments of 0.1. Source: Gilliam et al. (2007).

account in part for discrepancies in the results of studies of depression in TLE utilizing 1H-MRSI and FDG-PET.

Potential confounders of the results of any functional imaging studies in patients with epilepsy to be considered include the postictal effects of seizures, and chronic effects of antiepileptic medications.

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