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Motor cortex excitability in vascular depression
International Journal of Psychophysiology 82 (2011) 248–253
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Motor cortex excitability in vascular depression Rita Bella a, Raffaele Ferri b, Mariagiovanna Cantone a, Manuela Pennisi c, Giuseppe Lanza a, Giulia Malaguarnera a, Concetto Spampinato d, Daniela Giordano d, Alberto Raggi b, Giovanni Pennisi a,⁎ a
Department GF Ingrassia, Section of Neurosciences, University of Catania, Via Santa Sofia, 78-95123 Catania, Italy Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via Conte Ruggero, 73-94018 Troina (EN), Italy Department of Chemistry, University of Catania, Viale Andrea Doria, 6-95125 Catania, Italy d Department of Electrical, Electronics and Informatics Engineering, University of Catania, Viale Andrea Doria, 6-95125 Catania, Italy b c
a r t i c l e
i n f o
Article history: Received 20 April 2011 Received in revised form 6 August 2011 Accepted 4 September 2011 Available online 22 September 2011 Keywords: Vascular depression Major depression Motor cortex excitability Transcranial magnetic stimulation
a b s t r a c t The aim of this study was to evaluate excitatory/inhibitory intracortical circuit changes in patients with vascular depression, and whether there are any interhemispheric differences of motor cortical excitability. Fifteen vascular depressed elderly (VD), ten nondepressed subcortical vascular disease patients (SVD) and ten age-matched controls underwent bilateral motor threshold and paired-pulse studies. They were also assessed for their brain vascular burden at MRI and neuropsychological profile. Executive dysfunction and apathy were significantly higher in VD; we were unable to find significant differences in resting motor threshold, cortical silent period and paired-pulse curves between VD, SVD and controls, and between the two hemispheres in the VD group. Our findings might suggest that neurophysiological mechanisms underlying VD differ from those previously reported in Major Depression (reduced excitability in the left hemisphere) and seem to be similar to those of patients with SVD. Our findings also, support the “vascular depression” hypothesis, suggesting that in VD patients the depressive syndrome is not the primary disease but can be considered as one of the clinical manifestations in the wide symptom spectrum of the cerebral small vessel disease. © 2011 Elsevier B.V. All rights reserved.
1. Introduction The vascular depression hypothesis presenting clinically as a “depression-executive dysfunction syndrome of late life” (Alexopoulos et al., 2002) states that disruption of frontostriatal circuits by vascular lesions predisposes, precipitates, or perpetuates some late-life depressive syndromes. This notion is supported by clinical studies showing a close relationship between vascular disease and depression of late life and by numerous neuroimaging investigations reporting an increased prevalence and severity of white matter hyperintensities (WMHs) in individuals with geriatric depression, especially in those with late-onset illness (de Groot et al., 2000; O'Brien et al., 1996; Steffens et al., 1999). Neuropathological research has shown that deep WMHs have an ischemic basis, and such ischemic lesions are more frequently located at the level of dorsolateral prefrontal cortex in depressed subjects (Thomas et al., 2002), in the absence of any significant Alzheimer type or Lewy Body pathology. WMHs are more tightly associated than lacunar infarcts to depressive symptoms (O'Brien et al., 2006), poor antidepressant outcome
⁎ Corresponding author. Tel.: +39 0953782699; fax: +39 0953782808. E-mail address: [email protected] (G. Pennisi). 0167-8760/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpsycho.2011.09.006
(Bella et al., 2010; O'Brien et al., 1998), increased relapse and progression to chronic depression (Steffens et al., 2002), cognitive impairment and disability (Alexopoulos, 2005). Although the direction of causation between WMHs and depression has not yet been completely clarified, longitudinal studies shed light on the progression and predictive value of WMHs in depression (Teodorczuk et al., 2010). The effect of laterality of WMHs on depression is still controversial because while few reports have found frontal left-sided WMHs to be more predictive of depression (Tupler et al., 2002; Greenwald et al., 1998) others did not find any laterality effect (MacFall et al., 2001; O'Brien et al., 2006). In post-stroke depression the heterogeneity across the studies led to discrepant findings on the association between lesion location and post-stroke depression (Bhogal et al., 2004). On the contrary, in patients with nonvascular major depression, the majority of functional neuromaging studies found a hypometabolism and hypoperfusion of the left dorsolateral prefrontal cortex (Baxter et al., 1989; Bench et al., 1993; Martinot et al., 1990). These findings were extended by electroencephalography studies that demonstrated a decreased neural activity in the left frontal regions, as indicated by an increased alpha power (Debener et al., 2000; Salustri et al., 2007). Transcranial magnetic stimulation (TMS) studies are in favor of a reduced activation of both excitatory and inhibitory circuits in the left hemisphere in nonvascular major depression (Maeda et al., 2000; Lefaucheur et al., 2008). These
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findings had practical implication for the development of repetitive TMS (rTMS) protocols in the treatment of drug resistant nonvascular major depression (Padberg and George, 2009). TMS is a noninvasive technique initially employed to evaluate the integrity of the cortico-spinal tract and cortical motor areas. The development of new protocols of stimulation, such as paired-pulse and repetitive paradigms, has allowed to explore inhibitory and excitatory interactions of various motor and non-motor cortical regions, within and across the cerebral hemispheres. These applications provide information on the pathophysiology of the neuronal circuitry of different brain regions involved in cognitive processing in health and in various neuropsychiatric diseases, as well as on mechanisms of brain plastic changes and of in vivo effects of neuroactive drugs (Reis et al., 2008). A variety of TMS motor cortex excitability measures can be obtained, each related to distinct neurobiological processes. Motor threshold is believed to reflect the membrane excitability of corticospinal motor neurons, which is mainly dependent on the ion channel conductivity. Cortical silent period refers to a suppression of the electromyographic activity during a voluntary contraction of the target muscle and depends, at least in part, on inhibitory mechanisms at the level of the motor cortex, probably mediated by gamma-aminobutyric acid (GABA)-b receptors. Intracortical inhibitory and facilitatory interactions, as measured by the paired-pulse technique, are probably related to the balance of GABAergic, dopaminergic and glutamatergic transmissions (Ziemann, 2004). These TMS parameters are of valuable interest for our study, since their changes have been associated with depression. They are becoming accepted parameters to investigate the pathophysiology of various neuropsychiatric disorders involving the regulatory mechanisms of cortical excitability and have also been proposed for the early diagnosis of dementing processes, in order to monitor disease progression and treatment response (Pierantozzi et al., 2004; Alagona et al., 2001; Pennisi et al., 2002). Moreover, a new concept of motor cortex is emerging in which motor cortical output is influenced by non-primary motor areas, including ventral and dorsal premotor cortex, supplementary motor area and cingulate cortex (Reis et al., 2008). The clinical and neuroradiological profile of “vascular depression” seems to be well depicted; however, up to now neurophysiological studies providing data regarding cortical excitability and inhibitory and facilitatory modulation in brain activity are lacking. The few TMS studies on subcortical ischemic vascular disease patients did not find any changes in cortical excitability or interhemispheric asymmetries, whereas a pattern of increased cortical excitability was observed only in the presence of dementia (Di Lazzaro et al., 2008; Pennisi et al., 2010). Given the different biological substrates of vascular depression and major depression, it was hypothesized that these differences might be evident also at the level of TMS. Thus, the aim of this study was to examine cortical excitability and any interhemispheric difference in patients with vascular depression. 2. Methods 2.1. Subjects Fifteen vascular depressed (VD) elderly (mean age 70.5 ± 6.6 years), ten nondepressed patients with subcortical vascular disease (SVD) (mean age 70.8 ± 6.3) and ten age-matched controls (mean age 67.7 ± 3.9 years) were consecutively recruited at the Cerebrovascular Disease Center of the University of Catania. Depressed patients met the DSM-IV-TR diagnostic criteria for unipolar major depression. Patients and controls were treated for their vascular risk factors with anti-platelet or anticoagulant medications (aspirin, clopidogrel, warfarin), anti-hypertensive drugs (angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonist, diuretics, calcium channel blockers), cholesterol
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lowering medications (statins) and oral antidiabetic drugs or insulin. All patients and controls performed brain Magnetic Resonance Imaging (MRI) and both VD and SVD groups fulfilled the MRI criteria (Erkinjuntti et al., 2000) for SVD with predominant white matter lesions. Exclusion criteria were: history of major psychiatric illness (with the exception of personality disorders and anxiety, if secondary to depression); neurological disorders (i.e. Parkinson's disease, stroke, dementia, multiple sclerosis, etc.); history of head trauma or epilepsy; acute or chronic medical illness; endocrinopathies associated with depression or affecting cognitive functions; alcohol or drug abuse; use of drugs causing depressive symptoms (i.e. steroids, beta-blockers, clonidine); patients on treatment with antidepressant drugs; use of drugs able to modulate cortical excitability (i.e. benzodiazepines, antipsychotics, mood stabilizers); Mini Mental State Examination score b24 (Folstein et al., 1975), and conditions precluding MRI or TMS execution. Electroencephalography was performed to rule out predisposition to seizures. The study was approved by the local ethics committee and informed consent was obtained from all subjects. 2.2. Subject assessments Clinical and demographic assessments included age, gender, education, social and living conditions, presence of cerebrovascular risk factors, presence of neurological signs and symptoms, personal or family history of depression. The diagnostic evaluation was conducted by using the Structured Clinical Interview for DSM-IV and depressive symptoms were rated by means of the 17-items Hamilton Depression Rating Scale (Hamilton, 1960). Functional status was evaluated by basic and instrumental activities of daily living (Activity of Daily Living; Instrumental Activity of Daily Living). Subsequently, all patients underwent a neuropsychological battery, including the evaluation of the overall cognitive impairment (Mini Mental State Examination), global cognitive and functional status (Clinical Dementia Rating Scale) (Morris, 1993); Frontal Assessment Battery for the evaluation of different frontal lobe abilities (Appollonio et al., 2005); the Stroop Color–Word Test interference (normative values collected from an Italian population sample, Stroop T score ≤36.92 s; Stroop E errors ≤4.24) (Caffara et al., 2002), Apathy Scale (Strauss and Sperry, 2002). Cognitive assessment was performed by one of the authors (G.L.) blind to the hypothesis of the study. Brain MRI was acquired with a 1.5T General Electric system. The protocol included the T1-, T2-, proton density-weighted and Fluid Attenuated Inversion Recovery scans; slice thickness was 5 mm with 0.5 mm slice gap. The severity of deep white matter lesions was graded according to the visual scale of Fazekas: 0 = absence; 1 = punctuate foci; 2 = beginning confluence of foci; 3 = large confluent areas (Fazekas et al., 1987). 2.3. Transcranial magnetic stimulation procedures Motor Evoked Potentials (MEPs) of the right and left First Dorsal Interosseous muscles were elicited using a Magstim 200 stimulator (The Magstim Company, Whitland, Dyfed) connected to a 70 mm figure-of-eight coil. The coil was applied with the handle pointing backwards and laterally, at an angle of 45° to the sagittal plane, on the optimum site of stimulation which consistently yielded the largest MEP (hot spot). Electromyographic activity was recorded from a silver/silver-chloride surface active electrode placed over the motor point of the target muscle with the reference electrode placed distally at the metacarpophalangeal joint of the index finger. Motor responses were amplified and filtered (bandwidth 3–3000 Hz) using a Medelec Synergy (Oxford Instruments) system with gains of 100 μV and 5 mV/div. Resting Motor Threshold (rMT) was defined, according to the IFCN Committee recommendation (Rossini et al., 1994), as the lowest
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stimulus intensity able to elicit MEPs of an amplitude N50 μV in at least 5 of 10 trials, with the muscle at rest. Central motor conduction time was calculated by subtracting the conduction time in peripheral nerves, estimated by conventional F-wave techniques, from MEP latency obtained during moderate active muscle contraction (10–20% of maximum background force), at a stimulus intensity set at 130% of the rMT (Rossini et al., 1994). M and F waves were elicited by giving supramaximal electrical stimulation (constant current square wave pulse of 0.2 ms) to the ulnar nerve at wrist. The size of the MEPs was expressed as a percentage of supramaximal M wave amplitude (Amplitude ratio). Moreover, in order to assess spinal motor excitability, the mean amplitude of the F wave was measured in the target muscle. The cortical silent period was determined with an approximately 50% of maximum tonic voluntary contraction of the First Dorsal Interosseous muscles, induced by single TMS pulses delivered at 130% of rMT. The mean cortical silent period duration of ten rectified trials was calculated. Intracortical Inhibition (ICI) and Intracortical Facilitation (ICF) have been studied using the conditioning-test paradigm described by Kujirai et al. (1993) applying two magnetic stimuli through a Bistim module (The Magstim Company, Whitland, Dyfed) connected to a Cambridge Electronic Design Micro 1401 interface (Cambridge, UK). The conditioning stimulus was applied at 80% of the subject's rMT, and the intensity of the test stimulus was set at 130% of the rMT. The Interstimulus Intervals (ISIs) tested were 1, 3, 5, 7, 10 and 15 ms. Ten trials for each ISI, for the conditioning stimulus alone and for test stimulus alone, were recorded in a random way with an 8-second interval among each trial. The responses were expressed as the ratio of the MEP amplitude produced by paired stimulation to that produced by test stimulation alone. All measurements were conducted while subjects were seated in a comfortable chair with continuous electromyographic monitoring to ensure either a constant level of electromyographic activity during tonic contraction or complete relaxation at rest. Data were collected on a computer and stored for off-line analysis.
2.4. Statistical analysis The non-parametric Kruskal–Wallis ANOVA test was used for the comparison of clinical, neuropsychological and neurophysiological variables obtained from patients and controls (followed by the Mann–Whitney test, used as a post-hoc analysis, for the comparison between pairs of groups), and the χ 2 test for categorical variables. The Wilcoxon test for paired data sets was used for the comparison between left and right hemisphere of VD patients. Nonparametric statistics was needed because of the categorical nature of the neuropsychological testing results and of the non-Gaussian distribution of the results of the TMS studies. A p value lower than 0.05 was considered as statistically significant. 3. Results The demographic, clinical, neuropsychological and MRI characteristics of the 3 groups of subjects are summarized in Table 1. No differences were found in vascular burden at MRI and neuropsychological measures between VD and SVD patients, whereas there was a statistically significant difference between VD and SVD in Apathy Scale score (p b 0.001). As expected, significantly higher scores at the Stroop T and Stroop E were found in VD and SVD patients. As shown in Table 2, no statistically significant differences were found for rMT, cortical silent period, central motor conduction time and amplitude ratio between VD and SVD patients, and controls. No statistical differences were observed between the mean amplitude of the F wave in the three groups. No significant differences were found between the right and left values of motor cortico-spinal excitability in VD patients (Table 3). Fig. 1 shows the MEP amplitude at different ISIs obtained from the two hemispheres in the 3 groups of subjects. Conditioned MEPs amplitude at ISIs 10 ms from the left hemisphere was significantly larger in the SVD than VD (p b 0.05) and controls (p b 0.01). A significant loss of MEP inhibition at ISI 1 ms from the left hemisphere was observed
Table 1 Demographic, clinical, neuropsychological and MRI characteristics of the groups. Data are expressed as mean ± S.D and analyzed by means of the Kruskal–Wallis ANOVA or number and analyzed by means of the chi-square test (percentage of total). VD
Age (mean ± SD), years Educational level, years MMSE CDR ADL IADL Stroop T, s Stroop E FAB HDRS Apathy Scale
Gender (males/females) Hypertension Diabetes Hypercholesterolemia Coronaropathy Atrial fibrillation Smoking habit Neurological signs Familial hystory Personal hystory
70.5 ± 6.6 8 ± 5.7 26.4 ± 1.4 0 5.8 ± 0.4 7.3 ± 1.4 43.2 ± 16.5 3.5 ± 3 14.6 ± 2.4 14.9 ± 6.4 1.4 ± 0.4
7/8 11 (73.3%) 6 (40%) 10 (66.7%) 1 (6.7%) 1 (6.7%) 12 (80%) 5 (33.3%) 1 (6.7%) 1 (6.7%)
SVD
Controls
Kruskal–Wallis ANOVA H(2,35)
p=
70.8 ± 6.3 8.5 ± 5.2 27.5 ± 1.9 0 6 7.8 ± 0.4 41.1 ± 16 3.4 ± 3.5 14.5 ± 2.5 4.3 ± 2.1 0.4 ± 0.3
67.7 ± 3.9 10.1 ± 5.1 28.5 ± 1.9 0 6 7.8 ± 0.4 26.3 ± 11.8 0.9 ± 1.2 16.5 ± 1.9 4.9 ± 2.5 0.4 ± 0.4
1.665 2.393 10.492 0 4.250 0.406 7.279 6.586 5.529 25.443 21.771
0.435 0.302 0.0053 NS 0.119 0.816 0.026 0.037 0.063 0.00001 0.00001
6/4 9 (90%) 4 (40%) 6 (60%) 2 (20%) 2 (20%) 7 (70%) 4 (40%) 1 (10%) 1 (10%)
5/5 6 (60%) 1 (10%) 3 (30%) 0 (0%) 0 (0%) 5 (50%) 0 (0%) 1 (10%) 0 (0%)
Chi-square 0.44 2.37 2.98 3.43 2.67 2.67 2.52 4.98 0.12 0.97
p= 0.803 0.306 0.225 0.180 0.263 0.263 0.284 0.083 0.941 0.972
VD = vascular depression; SVD = subcortical vascular disease; MMSE = Mini Mental State Examination; CDR = Clinical Dementia Rating Scale; ADL = Activity of Daily Living; IADL = Instrumental Activity of Daily Living; Stroop T = Stroop Color–Word Test interference score time; Stroop E = Stroop Color–Word Test interference number of errors; FAB = Frontal Assessment Battery; HDRS = 17-items Hamilton Depression Rating Scale.
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Table 2 TMS parameters obtained from the patients and the control groups. Data are expressed as mean ± S.D. VD
SVD
Controls
Kruskal– Wallis ANOVA H(2,35) p =
Left
rMT CSP CMCT A ratio F wave amplitude
Right rMT CSP CMCT A ratio F wave amplitude
46.9 ± 10.61 46.4 ± 8.85 43.9 ± 5.72 68.9 ± 25.56 76.9 ± 19.95 60 ± 19 5.8 ± 0.98 5.5 ± 0.79 6.3 ± 1.39 0.4 ± 0.11 0.4 ± 0.13 0.4 ± 0.09 0.1 ± 0.1 0.1 ± 0.04 0.1 ± 0.05
2.211 5.299 2.000 1.115 2.432
0.593 0.170 0.368 0.573 0.296
46.1 ± 10.71 43.1 ± 5.53 43.8 ± 4.18 79.5 ± 40.24 82.1 ± 29.34 62.6 ± 19.03 5.9 ± 0.74 5.6 ± 0.43 5.4 ± 0.91 0.5 ± 0.12 0.4 ± 0.14 0.5 ± 0.11 0.1 ± 0.06 0.1 ± 0.1 0.1 ± 0.05
1.022 1.348 2.256 3.524 2.337
0.600 0.510 0.324 0.172 0.311
VD = vascular depression; SVD = subcortical vascular disease; rMT = resting motor threshold (%); CSP = cortical silent period (ms); CMCT = central motor conduction time (ms); A ratio = amplitude ratio; F wave amplitude (mV).
in VD and SVD than in controls (p b 0.01). There was no significant difference in paired-pulse curve between the hemispheres in VD group.
4. Discussion To our knowledge, this is the first neurophysiological study evaluating motor cortex excitability by means of single and paired-pulse TMS paradigms in patients with VD. Until now, TMS studies conducted on elderly patients with VD concern the efficacy and safety of rTMS applied to the dorsolateral prefrontal cortex for the treatment of depressive symptoms (Fabre et al., 2004; Jorge et al., 2008), which is known to be more chronic and treatment-resistant than early-onset depression. The increased low theta power in the subgenual anterior cingulate cortex predicts antidepressant efficacy of rTMS probably due to current spread from dorsolateral prefrontal cortex to neighboring areas connected to the subgenual anterior cingulate cortex (Narushima et al., 2010). Interestingly, our data on VD patients provide no evidence of overall changes of motor cortical excitability or interhemispheric asymmetry indexed by rMT. It should be taken into account that rMT reflects neuronal membrane excitability and represents the basic parameter for the study of cerebral excitability. These findings allow us to outline a pattern of cortical excitability clearly different from that of patients with nonvascular major depression. Most TMS studies of patients with nonvascular major depression, but not all (Navarro et al., 2009) reported an interhemispheric imbalance in frontal cortex activities, in favor of a reduced excitability of the motor cortex in the left hemisphere (Maeda et al., 2000; Fitzgerald et al., 2004; Bajbouj et al., 2006; Lefaucheur et al., 2008). The underlying mechanisms and the relevance
Table 3 TMS parameters obtained from the hemispheres in the VD group. Data are expressed as mean ± S.D. Left
rMT CSP CMCT A ratio
46.9 ± 10.61 68.9 ± 25.56 5.8 ± 0.98 0.4 ± 0.11
Right
46.1 ± 10.71 79.5 ± 40.24 5.9 ± 0.74 0.5 ± 0.12
Wilcoxon test T
pb
10.5 25.0 22.0 24.0
0.155 0.799 0.575 0.721
rMT = resting motor threshold (%); CSP = cortical silent period (ms); CMCT = central motor conduction time (ms); A ratio = amplitude ratio.
Fig. 1. MEP amplitude at different ISIs obtained from the two hemispheres in the 3 groups of subjects. Data are expressed as mean ± S.E. (whiskers). VD = vascular depression; SVD = subcortical vascular disease; MEP = Motor Evoked Potentials; ISI = Interstimulus Interval.
of these abnormalities are unclear since the heterogeneity of the groups and their medication status. Nevertheless asymmetry of motor cortical excitability might be related to the pathophysiology of nonvascular major depression. In addition, it seems that our VD patients did not exhibit impairment of the mechanisms regulating GABAergic intracortical inhibitory circuits, as shown by the normal cortical silent period duration and the inhibitory phenomenon measured by the paired-pulse paradigm (Chen et al., 2008). The significant reduction of intracortical inhibition observed at 1 ms ISI might probably be caused by a different mechanism other than GABAergic and probably related to the desynchronization of the descending volley, due to the relative refractory period of the corticospinal neurons (Hanajima et al., 2003). TMS studies of patients with nonvascular major depression have shown a significant reduction in the amount of both inhibitory (shortened cortical silent period and reduced ICI) and facilitatory (reduced ICF) inputs regarding the left frontal cortex compared to healthy controls and to the contralateral hemisphere (Bajbouj et al., 2006; Lefaucheur et al., 2008; Levinson et al., 2010). These results are consistent with the hypothesis of the GABAergic involvement in the pathophysiology of depression, as previously suggested by animal, neurochemical and neuroimaging studies (Brambilla et al., 2003; Croarkin et al., 2011). The lack of involvement of the inhibitory GABAergic intracortical mechanisms, suggested by ICI and cortical silent period measures in our patients, might provide a new and intriguing neurophysiological explanation for the different neurobiological processes underlying nonvascular major depression and VD. Moreover, a recent immunohistochemical study on the role of the GABAergic transmission in late-life depression did not find any change in two distinct GABA interneuron subpopulations within the dorsolateral prefrontal cortex (Khundakar et al., 2011). VD seems to arise from the progressive and sequential disruption of subtle connections implicated in mood-affect regulation and cognition. The characteristics of our patients are comparable with those of previous reports focused on elderly patients with major depression. They were aged, had a poor family history of depression, moderate psychopathology, impairment in the neuropsychological test. Risk factors are much the same as those reported for cerebrovascular disease with hypertension the most frequently observed. Psychomotor retardation, difficulties at work, apathy, lack of insight and executive dysfunction are the clinical presentation of our patients with depression. These mood and cognitive symptoms are thought to be a consequence of disruption, by vascular lesions, of the reciprocal connections between the prefrontal cortex and basal ganglia and
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between the prefrontal cortex and cerebellum (Levy and Dubois, 2006), although also frontal gray matter atrophy due to deafferentation could contribute to the development of the mood disturbance (Mueller et al., 2010). Serotonin is well documented to play a significant role in the pathophysiology of nonvascular major depression and other psychiatric disorders. Conversely, neuropathological studies in late-life depression did not find evidence of a loss of serotoninergic neurons in the dorsal raphe nucleus (Hendricksen et al., 2004) or reduction in serotonin transporter density at the level of the prefrontal cortex (Thomas et al., 2006). However, membrane excitability of pyramidal neurons is not or is poorly modulated by serotonin (Gerdelat-Mas et al., 2005). A growing body of evidence indicates that the glutamate neurotransmission, which is known to play a major role in neuronal plasticity, is disrupted in major depressive disorder, and that drugs targeting the N-methyl-D-aspartate receptor have shown antidepressant properties (Zarate et al., 2003). Reduction in glutamate/glutamine levels in the anterior cingulate cortex (Auer et al., 2000) and in the left cingulum (Pfleiderer et al., 2003) have been documented in adult depressed patients. In a recent postmortem study, Van Otterloo et al. (2009) did not find differences between older depressed patients and age-matched controls in laminar density of pyramidal (presumably glutamatergic) or nonpyramidal (GABAergic) neurons within the dorsolateral prefrontal cortex, whereas a previous work had observed a significant reduction of the density of pyramidal neurons in the orbitofrontal cortex of aged depressed patients (Rajkowska et al., 2005). Conversely, the role of the glutamatergic system in VD has yet to be elucidated. We observed a trend toward an enhancement of ICF in patients, although in VD it did not reach statistical significance. Although the meaning of this motor cortex facilitation is unknown, it might represent the expression of plasticity-related processes mediated by N-methyl-D-aspartate receptor activation, suggesting a compensatory role of ICF in response to vascular damage of the frontal cortical–subcortical circuits. The main limitation of this study is the relatively small number of patients, although they were very homogeneous in demographics, clinical and neuroradiological features and age-matched with controls without any white matter lesions at brain MRI, that are strikingly prevalent among elderly. In this study, the largest difference between VD and SVD patients was obtained for the left CSP (difference approximately 8) and the doubt that using a larger sample size a significant difference would be detected can arise. For this reason, we performed a power analysis on left CSP (as a probe) to determine which difference would have yielded a significant result with alpha 0.05 and a power of 80%. Based on the results observed, we used a standard deviation of 23 for this calculation and obtained that we would have needed a difference in the means of 30.5. This value is 3.8 times higher than the observed difference of 8 and suggests that even using larger groups we would not be able to reject the null hypothesis. Likewise, using the same parameters it turned out that we would have needed 131 subjects in each group to reach a significance at p = 0.05. Thus, in spite of the small sample size, the results of the present study seem to be clear, although they need to be further verified and confirmed by independent investigations with larger group sizes. Future studies combining TMS with electroencephalography may further clarify if the lack of cortical inhibition in vascular depression involves non motor areas, especially the dorsolateral prefrontal cortex. In conclusion, our findings suggest that the pattern of motor cortex excitability in VD differs from that previously reported in nonvascular major depression and is similar to that of patients with SVD (Pennisi et al., 2010). These data seem to support the “vascular depression hypothesis” as a different syndrome with respect to nonvascular major depression, suggesting that in VD patients the depressive syndrome is
probably not the primary disease but might be considered as one of the clinical manifestations in the wide symptom spectrum of cerebrovascular disease. The study of cortical excitability by means of TMS provides a potentially new window into the neurophysiological mechanisms behind vascular depression and its reciprocal relationship with subcortical vascular disease and vascular cognitive impairment. Moreover, it might be used as the basis for a better understanding of the course of geriatric depression and for the development of rTMS-based therapeutic protocols.
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Motor cortex excitability in vascular depression Rita Bella a, Raffaele Ferri b, Mariagiovanna Cantone a, Manuela Pennisi c, Giuseppe Lanza a, Giulia Malaguarnera a, Concetto Spampinato d, Daniela Giordano d, Alberto Raggi b, Giovanni Pennisi a,⁎ a
Department GF Ingrassia, Section of Neurosciences, University of Catania, Via Santa Sofia, 78-95123 Catania, Italy Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via Conte Ruggero, 73-94018 Troina (EN), Italy Department of Chemistry, University of Catania, Viale Andrea Doria, 6-95125 Catania, Italy d Department of Electrical, Electronics and Informatics Engineering, University of Catania, Viale Andrea Doria, 6-95125 Catania, Italy b c
a r t i c l e
i n f o
Article history: Received 20 April 2011 Received in revised form 6 August 2011 Accepted 4 September 2011 Available online 22 September 2011 Keywords: Vascular depression Major depression Motor cortex excitability Transcranial magnetic stimulation
a b s t r a c t The aim of this study was to evaluate excitatory/inhibitory intracortical circuit changes in patients with vascular depression, and whether there are any interhemispheric differences of motor cortical excitability. Fifteen vascular depressed elderly (VD), ten nondepressed subcortical vascular disease patients (SVD) and ten age-matched controls underwent bilateral motor threshold and paired-pulse studies. They were also assessed for their brain vascular burden at MRI and neuropsychological profile. Executive dysfunction and apathy were significantly higher in VD; we were unable to find significant differences in resting motor threshold, cortical silent period and paired-pulse curves between VD, SVD and controls, and between the two hemispheres in the VD group. Our findings might suggest that neurophysiological mechanisms underlying VD differ from those previously reported in Major Depression (reduced excitability in the left hemisphere) and seem to be similar to those of patients with SVD. Our findings also, support the “vascular depression” hypothesis, suggesting that in VD patients the depressive syndrome is not the primary disease but can be considered as one of the clinical manifestations in the wide symptom spectrum of the cerebral small vessel disease. © 2011 Elsevier B.V. All rights reserved.
1. Introduction The vascular depression hypothesis presenting clinically as a “depression-executive dysfunction syndrome of late life” (Alexopoulos et al., 2002) states that disruption of frontostriatal circuits by vascular lesions predisposes, precipitates, or perpetuates some late-life depressive syndromes. This notion is supported by clinical studies showing a close relationship between vascular disease and depression of late life and by numerous neuroimaging investigations reporting an increased prevalence and severity of white matter hyperintensities (WMHs) in individuals with geriatric depression, especially in those with late-onset illness (de Groot et al., 2000; O'Brien et al., 1996; Steffens et al., 1999). Neuropathological research has shown that deep WMHs have an ischemic basis, and such ischemic lesions are more frequently located at the level of dorsolateral prefrontal cortex in depressed subjects (Thomas et al., 2002), in the absence of any significant Alzheimer type or Lewy Body pathology. WMHs are more tightly associated than lacunar infarcts to depressive symptoms (O'Brien et al., 2006), poor antidepressant outcome
⁎ Corresponding author. Tel.: +39 0953782699; fax: +39 0953782808. E-mail address: [email protected] (G. Pennisi). 0167-8760/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpsycho.2011.09.006
(Bella et al., 2010; O'Brien et al., 1998), increased relapse and progression to chronic depression (Steffens et al., 2002), cognitive impairment and disability (Alexopoulos, 2005). Although the direction of causation between WMHs and depression has not yet been completely clarified, longitudinal studies shed light on the progression and predictive value of WMHs in depression (Teodorczuk et al., 2010). The effect of laterality of WMHs on depression is still controversial because while few reports have found frontal left-sided WMHs to be more predictive of depression (Tupler et al., 2002; Greenwald et al., 1998) others did not find any laterality effect (MacFall et al., 2001; O'Brien et al., 2006). In post-stroke depression the heterogeneity across the studies led to discrepant findings on the association between lesion location and post-stroke depression (Bhogal et al., 2004). On the contrary, in patients with nonvascular major depression, the majority of functional neuromaging studies found a hypometabolism and hypoperfusion of the left dorsolateral prefrontal cortex (Baxter et al., 1989; Bench et al., 1993; Martinot et al., 1990). These findings were extended by electroencephalography studies that demonstrated a decreased neural activity in the left frontal regions, as indicated by an increased alpha power (Debener et al., 2000; Salustri et al., 2007). Transcranial magnetic stimulation (TMS) studies are in favor of a reduced activation of both excitatory and inhibitory circuits in the left hemisphere in nonvascular major depression (Maeda et al., 2000; Lefaucheur et al., 2008). These
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findings had practical implication for the development of repetitive TMS (rTMS) protocols in the treatment of drug resistant nonvascular major depression (Padberg and George, 2009). TMS is a noninvasive technique initially employed to evaluate the integrity of the cortico-spinal tract and cortical motor areas. The development of new protocols of stimulation, such as paired-pulse and repetitive paradigms, has allowed to explore inhibitory and excitatory interactions of various motor and non-motor cortical regions, within and across the cerebral hemispheres. These applications provide information on the pathophysiology of the neuronal circuitry of different brain regions involved in cognitive processing in health and in various neuropsychiatric diseases, as well as on mechanisms of brain plastic changes and of in vivo effects of neuroactive drugs (Reis et al., 2008). A variety of TMS motor cortex excitability measures can be obtained, each related to distinct neurobiological processes. Motor threshold is believed to reflect the membrane excitability of corticospinal motor neurons, which is mainly dependent on the ion channel conductivity. Cortical silent period refers to a suppression of the electromyographic activity during a voluntary contraction of the target muscle and depends, at least in part, on inhibitory mechanisms at the level of the motor cortex, probably mediated by gamma-aminobutyric acid (GABA)-b receptors. Intracortical inhibitory and facilitatory interactions, as measured by the paired-pulse technique, are probably related to the balance of GABAergic, dopaminergic and glutamatergic transmissions (Ziemann, 2004). These TMS parameters are of valuable interest for our study, since their changes have been associated with depression. They are becoming accepted parameters to investigate the pathophysiology of various neuropsychiatric disorders involving the regulatory mechanisms of cortical excitability and have also been proposed for the early diagnosis of dementing processes, in order to monitor disease progression and treatment response (Pierantozzi et al., 2004; Alagona et al., 2001; Pennisi et al., 2002). Moreover, a new concept of motor cortex is emerging in which motor cortical output is influenced by non-primary motor areas, including ventral and dorsal premotor cortex, supplementary motor area and cingulate cortex (Reis et al., 2008). The clinical and neuroradiological profile of “vascular depression” seems to be well depicted; however, up to now neurophysiological studies providing data regarding cortical excitability and inhibitory and facilitatory modulation in brain activity are lacking. The few TMS studies on subcortical ischemic vascular disease patients did not find any changes in cortical excitability or interhemispheric asymmetries, whereas a pattern of increased cortical excitability was observed only in the presence of dementia (Di Lazzaro et al., 2008; Pennisi et al., 2010). Given the different biological substrates of vascular depression and major depression, it was hypothesized that these differences might be evident also at the level of TMS. Thus, the aim of this study was to examine cortical excitability and any interhemispheric difference in patients with vascular depression. 2. Methods 2.1. Subjects Fifteen vascular depressed (VD) elderly (mean age 70.5 ± 6.6 years), ten nondepressed patients with subcortical vascular disease (SVD) (mean age 70.8 ± 6.3) and ten age-matched controls (mean age 67.7 ± 3.9 years) were consecutively recruited at the Cerebrovascular Disease Center of the University of Catania. Depressed patients met the DSM-IV-TR diagnostic criteria for unipolar major depression. Patients and controls were treated for their vascular risk factors with anti-platelet or anticoagulant medications (aspirin, clopidogrel, warfarin), anti-hypertensive drugs (angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonist, diuretics, calcium channel blockers), cholesterol
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lowering medications (statins) and oral antidiabetic drugs or insulin. All patients and controls performed brain Magnetic Resonance Imaging (MRI) and both VD and SVD groups fulfilled the MRI criteria (Erkinjuntti et al., 2000) for SVD with predominant white matter lesions. Exclusion criteria were: history of major psychiatric illness (with the exception of personality disorders and anxiety, if secondary to depression); neurological disorders (i.e. Parkinson's disease, stroke, dementia, multiple sclerosis, etc.); history of head trauma or epilepsy; acute or chronic medical illness; endocrinopathies associated with depression or affecting cognitive functions; alcohol or drug abuse; use of drugs causing depressive symptoms (i.e. steroids, beta-blockers, clonidine); patients on treatment with antidepressant drugs; use of drugs able to modulate cortical excitability (i.e. benzodiazepines, antipsychotics, mood stabilizers); Mini Mental State Examination score b24 (Folstein et al., 1975), and conditions precluding MRI or TMS execution. Electroencephalography was performed to rule out predisposition to seizures. The study was approved by the local ethics committee and informed consent was obtained from all subjects. 2.2. Subject assessments Clinical and demographic assessments included age, gender, education, social and living conditions, presence of cerebrovascular risk factors, presence of neurological signs and symptoms, personal or family history of depression. The diagnostic evaluation was conducted by using the Structured Clinical Interview for DSM-IV and depressive symptoms were rated by means of the 17-items Hamilton Depression Rating Scale (Hamilton, 1960). Functional status was evaluated by basic and instrumental activities of daily living (Activity of Daily Living; Instrumental Activity of Daily Living). Subsequently, all patients underwent a neuropsychological battery, including the evaluation of the overall cognitive impairment (Mini Mental State Examination), global cognitive and functional status (Clinical Dementia Rating Scale) (Morris, 1993); Frontal Assessment Battery for the evaluation of different frontal lobe abilities (Appollonio et al., 2005); the Stroop Color–Word Test interference (normative values collected from an Italian population sample, Stroop T score ≤36.92 s; Stroop E errors ≤4.24) (Caffara et al., 2002), Apathy Scale (Strauss and Sperry, 2002). Cognitive assessment was performed by one of the authors (G.L.) blind to the hypothesis of the study. Brain MRI was acquired with a 1.5T General Electric system. The protocol included the T1-, T2-, proton density-weighted and Fluid Attenuated Inversion Recovery scans; slice thickness was 5 mm with 0.5 mm slice gap. The severity of deep white matter lesions was graded according to the visual scale of Fazekas: 0 = absence; 1 = punctuate foci; 2 = beginning confluence of foci; 3 = large confluent areas (Fazekas et al., 1987). 2.3. Transcranial magnetic stimulation procedures Motor Evoked Potentials (MEPs) of the right and left First Dorsal Interosseous muscles were elicited using a Magstim 200 stimulator (The Magstim Company, Whitland, Dyfed) connected to a 70 mm figure-of-eight coil. The coil was applied with the handle pointing backwards and laterally, at an angle of 45° to the sagittal plane, on the optimum site of stimulation which consistently yielded the largest MEP (hot spot). Electromyographic activity was recorded from a silver/silver-chloride surface active electrode placed over the motor point of the target muscle with the reference electrode placed distally at the metacarpophalangeal joint of the index finger. Motor responses were amplified and filtered (bandwidth 3–3000 Hz) using a Medelec Synergy (Oxford Instruments) system with gains of 100 μV and 5 mV/div. Resting Motor Threshold (rMT) was defined, according to the IFCN Committee recommendation (Rossini et al., 1994), as the lowest
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stimulus intensity able to elicit MEPs of an amplitude N50 μV in at least 5 of 10 trials, with the muscle at rest. Central motor conduction time was calculated by subtracting the conduction time in peripheral nerves, estimated by conventional F-wave techniques, from MEP latency obtained during moderate active muscle contraction (10–20% of maximum background force), at a stimulus intensity set at 130% of the rMT (Rossini et al., 1994). M and F waves were elicited by giving supramaximal electrical stimulation (constant current square wave pulse of 0.2 ms) to the ulnar nerve at wrist. The size of the MEPs was expressed as a percentage of supramaximal M wave amplitude (Amplitude ratio). Moreover, in order to assess spinal motor excitability, the mean amplitude of the F wave was measured in the target muscle. The cortical silent period was determined with an approximately 50% of maximum tonic voluntary contraction of the First Dorsal Interosseous muscles, induced by single TMS pulses delivered at 130% of rMT. The mean cortical silent period duration of ten rectified trials was calculated. Intracortical Inhibition (ICI) and Intracortical Facilitation (ICF) have been studied using the conditioning-test paradigm described by Kujirai et al. (1993) applying two magnetic stimuli through a Bistim module (The Magstim Company, Whitland, Dyfed) connected to a Cambridge Electronic Design Micro 1401 interface (Cambridge, UK). The conditioning stimulus was applied at 80% of the subject's rMT, and the intensity of the test stimulus was set at 130% of the rMT. The Interstimulus Intervals (ISIs) tested were 1, 3, 5, 7, 10 and 15 ms. Ten trials for each ISI, for the conditioning stimulus alone and for test stimulus alone, were recorded in a random way with an 8-second interval among each trial. The responses were expressed as the ratio of the MEP amplitude produced by paired stimulation to that produced by test stimulation alone. All measurements were conducted while subjects were seated in a comfortable chair with continuous electromyographic monitoring to ensure either a constant level of electromyographic activity during tonic contraction or complete relaxation at rest. Data were collected on a computer and stored for off-line analysis.
2.4. Statistical analysis The non-parametric Kruskal–Wallis ANOVA test was used for the comparison of clinical, neuropsychological and neurophysiological variables obtained from patients and controls (followed by the Mann–Whitney test, used as a post-hoc analysis, for the comparison between pairs of groups), and the χ 2 test for categorical variables. The Wilcoxon test for paired data sets was used for the comparison between left and right hemisphere of VD patients. Nonparametric statistics was needed because of the categorical nature of the neuropsychological testing results and of the non-Gaussian distribution of the results of the TMS studies. A p value lower than 0.05 was considered as statistically significant. 3. Results The demographic, clinical, neuropsychological and MRI characteristics of the 3 groups of subjects are summarized in Table 1. No differences were found in vascular burden at MRI and neuropsychological measures between VD and SVD patients, whereas there was a statistically significant difference between VD and SVD in Apathy Scale score (p b 0.001). As expected, significantly higher scores at the Stroop T and Stroop E were found in VD and SVD patients. As shown in Table 2, no statistically significant differences were found for rMT, cortical silent period, central motor conduction time and amplitude ratio between VD and SVD patients, and controls. No statistical differences were observed between the mean amplitude of the F wave in the three groups. No significant differences were found between the right and left values of motor cortico-spinal excitability in VD patients (Table 3). Fig. 1 shows the MEP amplitude at different ISIs obtained from the two hemispheres in the 3 groups of subjects. Conditioned MEPs amplitude at ISIs 10 ms from the left hemisphere was significantly larger in the SVD than VD (p b 0.05) and controls (p b 0.01). A significant loss of MEP inhibition at ISI 1 ms from the left hemisphere was observed
Table 1 Demographic, clinical, neuropsychological and MRI characteristics of the groups. Data are expressed as mean ± S.D and analyzed by means of the Kruskal–Wallis ANOVA or number and analyzed by means of the chi-square test (percentage of total). VD
Age (mean ± SD), years Educational level, years MMSE CDR ADL IADL Stroop T, s Stroop E FAB HDRS Apathy Scale
Gender (males/females) Hypertension Diabetes Hypercholesterolemia Coronaropathy Atrial fibrillation Smoking habit Neurological signs Familial hystory Personal hystory
70.5 ± 6.6 8 ± 5.7 26.4 ± 1.4 0 5.8 ± 0.4 7.3 ± 1.4 43.2 ± 16.5 3.5 ± 3 14.6 ± 2.4 14.9 ± 6.4 1.4 ± 0.4
7/8 11 (73.3%) 6 (40%) 10 (66.7%) 1 (6.7%) 1 (6.7%) 12 (80%) 5 (33.3%) 1 (6.7%) 1 (6.7%)
SVD
Controls
Kruskal–Wallis ANOVA H(2,35)
p=
70.8 ± 6.3 8.5 ± 5.2 27.5 ± 1.9 0 6 7.8 ± 0.4 41.1 ± 16 3.4 ± 3.5 14.5 ± 2.5 4.3 ± 2.1 0.4 ± 0.3
67.7 ± 3.9 10.1 ± 5.1 28.5 ± 1.9 0 6 7.8 ± 0.4 26.3 ± 11.8 0.9 ± 1.2 16.5 ± 1.9 4.9 ± 2.5 0.4 ± 0.4
1.665 2.393 10.492 0 4.250 0.406 7.279 6.586 5.529 25.443 21.771
0.435 0.302 0.0053 NS 0.119 0.816 0.026 0.037 0.063 0.00001 0.00001
6/4 9 (90%) 4 (40%) 6 (60%) 2 (20%) 2 (20%) 7 (70%) 4 (40%) 1 (10%) 1 (10%)
5/5 6 (60%) 1 (10%) 3 (30%) 0 (0%) 0 (0%) 5 (50%) 0 (0%) 1 (10%) 0 (0%)
Chi-square 0.44 2.37 2.98 3.43 2.67 2.67 2.52 4.98 0.12 0.97
p= 0.803 0.306 0.225 0.180 0.263 0.263 0.284 0.083 0.941 0.972
VD = vascular depression; SVD = subcortical vascular disease; MMSE = Mini Mental State Examination; CDR = Clinical Dementia Rating Scale; ADL = Activity of Daily Living; IADL = Instrumental Activity of Daily Living; Stroop T = Stroop Color–Word Test interference score time; Stroop E = Stroop Color–Word Test interference number of errors; FAB = Frontal Assessment Battery; HDRS = 17-items Hamilton Depression Rating Scale.
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251
Table 2 TMS parameters obtained from the patients and the control groups. Data are expressed as mean ± S.D. VD
SVD
Controls
Kruskal– Wallis ANOVA H(2,35) p =
Left
rMT CSP CMCT A ratio F wave amplitude
Right rMT CSP CMCT A ratio F wave amplitude
46.9 ± 10.61 46.4 ± 8.85 43.9 ± 5.72 68.9 ± 25.56 76.9 ± 19.95 60 ± 19 5.8 ± 0.98 5.5 ± 0.79 6.3 ± 1.39 0.4 ± 0.11 0.4 ± 0.13 0.4 ± 0.09 0.1 ± 0.1 0.1 ± 0.04 0.1 ± 0.05
2.211 5.299 2.000 1.115 2.432
0.593 0.170 0.368 0.573 0.296
46.1 ± 10.71 43.1 ± 5.53 43.8 ± 4.18 79.5 ± 40.24 82.1 ± 29.34 62.6 ± 19.03 5.9 ± 0.74 5.6 ± 0.43 5.4 ± 0.91 0.5 ± 0.12 0.4 ± 0.14 0.5 ± 0.11 0.1 ± 0.06 0.1 ± 0.1 0.1 ± 0.05
1.022 1.348 2.256 3.524 2.337
0.600 0.510 0.324 0.172 0.311
VD = vascular depression; SVD = subcortical vascular disease; rMT = resting motor threshold (%); CSP = cortical silent period (ms); CMCT = central motor conduction time (ms); A ratio = amplitude ratio; F wave amplitude (mV).
in VD and SVD than in controls (p b 0.01). There was no significant difference in paired-pulse curve between the hemispheres in VD group.
4. Discussion To our knowledge, this is the first neurophysiological study evaluating motor cortex excitability by means of single and paired-pulse TMS paradigms in patients with VD. Until now, TMS studies conducted on elderly patients with VD concern the efficacy and safety of rTMS applied to the dorsolateral prefrontal cortex for the treatment of depressive symptoms (Fabre et al., 2004; Jorge et al., 2008), which is known to be more chronic and treatment-resistant than early-onset depression. The increased low theta power in the subgenual anterior cingulate cortex predicts antidepressant efficacy of rTMS probably due to current spread from dorsolateral prefrontal cortex to neighboring areas connected to the subgenual anterior cingulate cortex (Narushima et al., 2010). Interestingly, our data on VD patients provide no evidence of overall changes of motor cortical excitability or interhemispheric asymmetry indexed by rMT. It should be taken into account that rMT reflects neuronal membrane excitability and represents the basic parameter for the study of cerebral excitability. These findings allow us to outline a pattern of cortical excitability clearly different from that of patients with nonvascular major depression. Most TMS studies of patients with nonvascular major depression, but not all (Navarro et al., 2009) reported an interhemispheric imbalance in frontal cortex activities, in favor of a reduced excitability of the motor cortex in the left hemisphere (Maeda et al., 2000; Fitzgerald et al., 2004; Bajbouj et al., 2006; Lefaucheur et al., 2008). The underlying mechanisms and the relevance
Table 3 TMS parameters obtained from the hemispheres in the VD group. Data are expressed as mean ± S.D. Left
rMT CSP CMCT A ratio
46.9 ± 10.61 68.9 ± 25.56 5.8 ± 0.98 0.4 ± 0.11
Right
46.1 ± 10.71 79.5 ± 40.24 5.9 ± 0.74 0.5 ± 0.12
Wilcoxon test T
pb
10.5 25.0 22.0 24.0
0.155 0.799 0.575 0.721
rMT = resting motor threshold (%); CSP = cortical silent period (ms); CMCT = central motor conduction time (ms); A ratio = amplitude ratio.
Fig. 1. MEP amplitude at different ISIs obtained from the two hemispheres in the 3 groups of subjects. Data are expressed as mean ± S.E. (whiskers). VD = vascular depression; SVD = subcortical vascular disease; MEP = Motor Evoked Potentials; ISI = Interstimulus Interval.
of these abnormalities are unclear since the heterogeneity of the groups and their medication status. Nevertheless asymmetry of motor cortical excitability might be related to the pathophysiology of nonvascular major depression. In addition, it seems that our VD patients did not exhibit impairment of the mechanisms regulating GABAergic intracortical inhibitory circuits, as shown by the normal cortical silent period duration and the inhibitory phenomenon measured by the paired-pulse paradigm (Chen et al., 2008). The significant reduction of intracortical inhibition observed at 1 ms ISI might probably be caused by a different mechanism other than GABAergic and probably related to the desynchronization of the descending volley, due to the relative refractory period of the corticospinal neurons (Hanajima et al., 2003). TMS studies of patients with nonvascular major depression have shown a significant reduction in the amount of both inhibitory (shortened cortical silent period and reduced ICI) and facilitatory (reduced ICF) inputs regarding the left frontal cortex compared to healthy controls and to the contralateral hemisphere (Bajbouj et al., 2006; Lefaucheur et al., 2008; Levinson et al., 2010). These results are consistent with the hypothesis of the GABAergic involvement in the pathophysiology of depression, as previously suggested by animal, neurochemical and neuroimaging studies (Brambilla et al., 2003; Croarkin et al., 2011). The lack of involvement of the inhibitory GABAergic intracortical mechanisms, suggested by ICI and cortical silent period measures in our patients, might provide a new and intriguing neurophysiological explanation for the different neurobiological processes underlying nonvascular major depression and VD. Moreover, a recent immunohistochemical study on the role of the GABAergic transmission in late-life depression did not find any change in two distinct GABA interneuron subpopulations within the dorsolateral prefrontal cortex (Khundakar et al., 2011). VD seems to arise from the progressive and sequential disruption of subtle connections implicated in mood-affect regulation and cognition. The characteristics of our patients are comparable with those of previous reports focused on elderly patients with major depression. They were aged, had a poor family history of depression, moderate psychopathology, impairment in the neuropsychological test. Risk factors are much the same as those reported for cerebrovascular disease with hypertension the most frequently observed. Psychomotor retardation, difficulties at work, apathy, lack of insight and executive dysfunction are the clinical presentation of our patients with depression. These mood and cognitive symptoms are thought to be a consequence of disruption, by vascular lesions, of the reciprocal connections between the prefrontal cortex and basal ganglia and
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between the prefrontal cortex and cerebellum (Levy and Dubois, 2006), although also frontal gray matter atrophy due to deafferentation could contribute to the development of the mood disturbance (Mueller et al., 2010). Serotonin is well documented to play a significant role in the pathophysiology of nonvascular major depression and other psychiatric disorders. Conversely, neuropathological studies in late-life depression did not find evidence of a loss of serotoninergic neurons in the dorsal raphe nucleus (Hendricksen et al., 2004) or reduction in serotonin transporter density at the level of the prefrontal cortex (Thomas et al., 2006). However, membrane excitability of pyramidal neurons is not or is poorly modulated by serotonin (Gerdelat-Mas et al., 2005). A growing body of evidence indicates that the glutamate neurotransmission, which is known to play a major role in neuronal plasticity, is disrupted in major depressive disorder, and that drugs targeting the N-methyl-D-aspartate receptor have shown antidepressant properties (Zarate et al., 2003). Reduction in glutamate/glutamine levels in the anterior cingulate cortex (Auer et al., 2000) and in the left cingulum (Pfleiderer et al., 2003) have been documented in adult depressed patients. In a recent postmortem study, Van Otterloo et al. (2009) did not find differences between older depressed patients and age-matched controls in laminar density of pyramidal (presumably glutamatergic) or nonpyramidal (GABAergic) neurons within the dorsolateral prefrontal cortex, whereas a previous work had observed a significant reduction of the density of pyramidal neurons in the orbitofrontal cortex of aged depressed patients (Rajkowska et al., 2005). Conversely, the role of the glutamatergic system in VD has yet to be elucidated. We observed a trend toward an enhancement of ICF in patients, although in VD it did not reach statistical significance. Although the meaning of this motor cortex facilitation is unknown, it might represent the expression of plasticity-related processes mediated by N-methyl-D-aspartate receptor activation, suggesting a compensatory role of ICF in response to vascular damage of the frontal cortical–subcortical circuits. The main limitation of this study is the relatively small number of patients, although they were very homogeneous in demographics, clinical and neuroradiological features and age-matched with controls without any white matter lesions at brain MRI, that are strikingly prevalent among elderly. In this study, the largest difference between VD and SVD patients was obtained for the left CSP (difference approximately 8) and the doubt that using a larger sample size a significant difference would be detected can arise. For this reason, we performed a power analysis on left CSP (as a probe) to determine which difference would have yielded a significant result with alpha 0.05 and a power of 80%. Based on the results observed, we used a standard deviation of 23 for this calculation and obtained that we would have needed a difference in the means of 30.5. This value is 3.8 times higher than the observed difference of 8 and suggests that even using larger groups we would not be able to reject the null hypothesis. Likewise, using the same parameters it turned out that we would have needed 131 subjects in each group to reach a significance at p = 0.05. Thus, in spite of the small sample size, the results of the present study seem to be clear, although they need to be further verified and confirmed by independent investigations with larger group sizes. Future studies combining TMS with electroencephalography may further clarify if the lack of cortical inhibition in vascular depression involves non motor areas, especially the dorsolateral prefrontal cortex. In conclusion, our findings suggest that the pattern of motor cortex excitability in VD differs from that previously reported in nonvascular major depression and is similar to that of patients with SVD (Pennisi et al., 2010). These data seem to support the “vascular depression hypothesis” as a different syndrome with respect to nonvascular major depression, suggesting that in VD patients the depressive syndrome is
probably not the primary disease but might be considered as one of the clinical manifestations in the wide symptom spectrum of cerebrovascular disease. The study of cortical excitability by means of TMS provides a potentially new window into the neurophysiological mechanisms behind vascular depression and its reciprocal relationship with subcortical vascular disease and vascular cognitive impairment. Moreover, it might be used as the basis for a better understanding of the course of geriatric depression and for the development of rTMS-based therapeutic protocols.
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