Different patterns of cortical excitability in major depression and vascular depression: a transcranial magnetic stimulation study

A sample of 11 patients with VD (6 males and 5 females; mean age, 67.72 ± 3.29 years; mean education, 7.91 ± 5.75 years), 11 drug-resistant recurrent patients with MD without SVD at MRI (5 males and 6 females; mean age, 57.18 ± 7.12; mean education, 12.18 ± 5.98) and 11 age-matched controls (6 males and 5 females; mean age, 67.36 ± 3.75 years; mean education, 9.64 ± 5.08) were consecutively recruited from the Cerebrovascular Disease Center and from the Department of Psychiatry of the University of Catania (Italy).

VD was defined according to the proposed clinical and neuroradiological diagnostic criteria as follows: evidence of vascular risk factors; depression onset after the age of 65 or change in course of depression after vascular disease in people with early-onset depression; presence of some of the following features: cognitive impairment (consisting of, but not limited to, disturbance of executive functions), psychomotor retardation, limited depressive ideation, poor insight, disability, absence of family history of mood disorders, and presence of cerebrovascular disease on neuroimaging [2, 31]. VD patients fulfilled the brain MRI criteria for SVD [32], including extending periventricular and deep WMLs or multiple lacunes in deep grey matter, and at least moderate WMLs. VD patients had a primary diagnosis of a current major depressive episode as assessed by the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I). They 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, dihydropyridine calcium channel blockers), cholesterol lowering medications (statins), and oral antidiabetic drugs or insulin. No patients had focal motor deficits, but a slight reflex asymmetry was present in three patients. Mean age at depression onset in the VD patients was 62.27 ± 5.04 years. No patients were on antidepressant treatment or other psychotropic medicaments.

Drug-resistant MD patients met the DSM-IV-TR clinical diagnostic criteria for recurrent MD as assessed by the SCID-I, and showed a poor response in the course of the current depressive episode (mean duration, 4.33 ± 2.50 months). We defined treatment resistance as drug-resistance to three adequate courses of antidepressants from at least two different classes during the current major depressive episode [33, 34].

As shown in Table 1, the pharmacological regimen at the time of the study was: Selective Serotonin Reuptake Inhibitors, Tricyclic Antidepressant, Atypical Antipsychotic Drugs; Serotonin Noradrenaline Reuptake Inhibitors, Tricyclic Antidepressant, Atypical Antipsychotic Drugs. Seven MD patients were on zolpidem. The pharmacotherapy was unchanged throughout the course of the study. Mean age at depression onset in MD patients was 27.82 ± 7.32 years and, including the current episode, 6 patients experienced four major depressive episodes, whereas the remaining 5 patients were diagnosed with five or more episodes.

All patients were right-handed, with no history of brain trauma or seizures, and their general and neurological examination was unremarkable. Exclusion criteria were as follows: any non-mood psychotic disorder, chronic medical illness, endocrinopathies other than diabetes associated with depression or affecting cognitive functions (such as thyroid diseases), alcohol or drug abuse, use of drugs causing depressive symptoms (i.e. steroids, beta-blockers, clonidine), Mini Mental State Examination (MMSE) score <24, cases with cortical and/or cortico-subcortical non-lacunar territorial infarcts, borderzone infarcts, haemorrhages, signs of normal pressure hydrocephalus and specific causes of WMLs, and any condition precluding MRI or TMS execution. This study was approved by the local ethics committee based at the “Policlinico-Vittorio Emanuele” University Hospital of Catania (Italy), and all patients provided written informed consent.

All participants underwent a neuropsychological battery including the MMSE as a screening test for overall cognitive impairment, Clinical Dementia Rating Scale for the global cognitive and functional status, Frontal Assessment Battery and the Stroop Color-Word Test interference (normative values were collected from an Italian population sample, Stroop T score, ≤36.92 s; Stroop E errors, ≤4.24) [35] for the evaluation of different frontal lobe abilities, and the 17-item Hamilton Rating Scale for Depression (HRSD-17) for the rating of depressive symptoms. Functional status was evaluated by basic and instrumental activities of daily living (Activity of Daily Living; Instrumental Activity of Daily Living). The physical state of the control subjects was evaluated by general and neurological examinations; their mental state, assessed by means of the SCID-I, was unremarkable. All patients and controls underwent brain MRI scans, acquired using a 1.5 T General Electric system, before inclusion into the TMS study. The protocol included T1-, T2-, proton density-weighted and fluid-attenuated inversion recovery scans; slice thickness was 5 mm with a 0.5 mm slice gap. In the VD group, the severity of deep WMLs was graded according to the visual scale of Fazekas: 0 = absence; 1 = punctuate foci; 2 = beginning confluence of foci; 3 = large confluent areas [36].

MEPs of the right and left first dorsal interosseous (FDI) muscles as well as single-pulse TMS measures of cortical excitability were elicited using a Magstim 200 stimulator (The Magstim Company, Whitland, Dyfed, UK) 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 that consistently yielded the largest MEP (“hot spot”). Electromyographic activity was recorded from silver/silverchloride surface active electrodes 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) with gains of 100 μV and 5 mV/div.

The rMT was defined, according to the IFCN Committee recommendation [37], as the lowest stimulus intensity able to elicit MEPs of an amplitude >50 μV in at least 5 out of 10 trials, with the muscle at rest. The CSP was determined with an approximately 50% of maximum tonic voluntary contraction of the FDI muscles, induced by single TMS pulses delivered at 130% of rMT. The mean CSP duration of five rectified trials was calculated. Central motor conduction time (CMCT) 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 [37]. M and F waves were elicited by applying supramaximal electrical stimulation (constant current square-wave pulse of 0.2 ms) to the ulnar nerve at the wrist. The size of MEPs was expressed as a percentage of the supramaximal M wave amplitude (Amplitude ratio). Moreover, to assess spinal motor excitability, the mean amplitude of the F wave was measured in the target muscle. ICI and ICF were studied using the conditioning-test paradigm described by Kujirai et al. [38] through a Bistim module (The Magstim Company) connected to a Cambridge Electronic DesignMicro 1401 interface (Cambridge, UK). The procedure consisted of applying two magnetic stimuli in rapid succession through two magnetic stimulators connected to each other. 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 ISIs tested were 1, 3, 5, 7, 10, and 15 ms. Ten trials for each ISI were recorded randomly with an 8-second interval between each trial. The responses were expressed as the ratio of the MEP amplitude produced by paired stimulation to that produced by test stimulation alone. The use of a Bistim module was limited to the paired-pulse TMS measurements only, whereas all other investigations were performed using the single-pulse technique. 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 with software ad hoc for off-line analysis [39]. All procedures described above were performed in the same laboratory and situation, by the same operators for each subject at the same time during the day (approximately 3–5 pm).

The non-parametric Kruskal-Wallis ANOVA test was used for comparison of clinical, neuropsychological, and neurophysiological variables obtained from patients and controls (followed by the Mann–Whitney test for post-hoc analysis for the comparison between pairs of groups), and the χ2 test was used for categorical variables. The Wilcoxon test for paired data sets was used for the comparison between hemispheres of patients and controls. Nonparametric statistics were used because of the categorical nature of the neuropsychological testing results, and the non-Gaussian distribution of the results of the TMS studies. A p value lower than 0.05 was considered statistically significant.