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Hypoesthesia of the malleolus as a soft sign in depression
Journal of Affective Disorders 171 (2015) 128–131
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Brief report
Hypoesthesia of the malleolus as a soft sign in depression Lorenzo Livianos a,b,c, Pablo I. González-Valls a, Ana C. García-Blanco a,n, Helena Tobella a, Ignacio Díaz-Alonso a, Núria Alberola a, Susana García-Aznar a, Ramón Bellot a, Vanessa Saiz a, Lourdes Ros a a
Department of Psychiatry, La Fe University and Polytechnic Hospital, 46010 Valencia, Spain University of Valencia, Department of Medicine, Valencia, Spain c CIBERESP, Spain b
art ic l e i nf o
a b s t r a c t
Article history: Received 15 June 2014 Received in revised form 15 September 2014 Accepted 20 September 2014 Available online 30 September 2014
Background: Physical signs often are present in many psychiatric conditions, making up a fundamental part of them and accompanying the psychiatric manifestations themselves. Identifying minor neurological signs is especially of interest due to they are easily accessible through simple neurological examination and could be a useful if underused tool for the diagnostic process and patient therapy. Method: A group of depressed patients (n ¼ 85) and group of healthy individuals (n ¼101) that served as control were examined using the Wartenberg wheel, a medical device for neurological use, in order to determine the presence of hypoesthesia on both sides of their ankles. Results: The data revealed: i) patients with depression are generally more likely to present malleolar hypoesthesia than healthy participants; and ii) participants who presented malleolar hypoesthesia presented greater depressive symptomatology as well as greater anxiety symptomatology at the time of assessment. Limitations: Although all patients in this study were taking psychotropic medication, anxiolytics and antidepressants are not associated with skin sensitivity. As is usual, the categorization of hypoesthesia is based on participant subjectivity. However, this subjectivity cannot explain the differences between depressed patients and healthy individuals. Conclusions: The present findings corroborate that localized tactile sensitivity is altered in depression and correlates with anxiety-depressive symptomatology, even on a subclinical level. The observation of neurological soft signs such as the detection of malleolar hypoesthesia in patients with depressive symptomatology is easily accessible using a simple neurological examination, and it could became a powerful tool that could provide objective information on affective disorders. & 2014 Published by Elsevier B.V.
Keywords: Depression Neurological soft signs Tactile sensitivity Hypoesthesia
1. Introduction The lack of objective diagnostic tests has traditionally been one of psychiatry's main disadvantages compared to other fields of medicine. However, mental illness is ocassionally inseparable from certain physical signs, and therefore, identifying them could be a useful if underused tool for the diagnostic process. In the case of minor neurological signs, although they may be aspecific, they are easily accessible through simple procedures. However, as Gupta et al. (2002) point out, the current diagnostic manuals, such as the ICD-10 (World Health Organisation, 1992), have not
n
Corresponding author. Tel.: þ 34 961 245553. E-mail address: [email protected] (A.C. García-Blanco).
http://dx.doi.org/10.1016/j.jad.2014.09.034 0165-0327/& 2014 Published by Elsevier B.V.
sufficiently addressed the presence of physical signs, particularly in depressive disorders and anxiety disorders. Actually, in the study of affective disorders there have been numerous findings in the literature concerning physical signs or biomarkers; from Otto Veraguth's 1935 description of the wellknown palpebral fold (Sadock et al., 2007) to the most current discoveries in the field of neuroimaging (see Diener et al. (2012), for a review). Depression has been associated with different measurable biomarkers in the laboratory related to the hypothalamic–pituitary–adrenocortical axis (see Carroll (1985), for dexamethasone suppression; see Rush et al. (1997), for reduced TRH; see Steiger and Kimura (2010), for sleep alterations—which would be regulated by this axis). Other endocrine parameters have also been analyzed, such as insulin resistance (Schmidt et al., 2011), sex steroids, GH, melatonin or prolactin (Sadock et al., 2007), although with inconsistent results. Metabolic markers such as a decrease in
L. Livianos et al. / Journal of Affective Disorders 171 (2015) 128–131
serotonin transporter, hypocholesterolemia and a decrease in the phosphorylation of the CREB protein (Caruncho and RiveraBaltanás, 2010). Another recent area of interest in depression is that of inflammation and its cytokines (Miller et al., 2009). In the field of neuroimaging, more relevant findings relative to greater levels of depression have been discovered in: ii) structural neuroimaging (subcortical hyperintensities in periventricular regions, the basal ganglia and the thalamus, as well as reductions in the volume of the frontal lobes, hippocampus and basal ganglia; Arnone et al., 2012); and ii) functional neuroimaging (hypometabolism in dorsolateral prefrontal area, anterior cingulate cortex and the temporal lobes; Mayberg et al., 2012). All of the biological signs listed here have been of significant importance up until now in the field of research, but not in common clinical practice. This is due to several factors: i) laboratory and neuroimaging techniques are expensive tests that cannot be used as everyday diagnostic tests; and ii) the results are not completely consistent. Therefore, the analysis of minor neurological signs is especially of interest. The observation of these signs does not require sophisticated methods; neurological examination is a basic tool in medicine, and it can provide objective information on the underlying illness. Though it is true that in the scientific literature there exist many studies on schizophrenia that have associated it with different minor neurological signs (Krebs and Mouchet, 2007), we know little about their relationship with affective disorders. This line of research on depression has provided particularly interesting data relative to pain and sensory perception. Bleuler (1916) described alterations of the senses in neurotic and melancholic states such as hyperesthesia and hyper-, hypo- and analgesia. Over the last few years, research has been conducted that has demonstrated objective alterations of the senses in depressed patients. Recent studies have found a reduction of the perception of contrast measured via electroretinogram in these patients that correlated with the severity of the depression (Bubl et al., 2010). Olfactory capacity has also been evaluated and alterations have also been detected in the sensitivity and identification of odors (Atanasova et al., 2008). As for the relationship between depression and pain, several studies indicate that the perception of painful stimuli has a higher threshold in depressed subjects than in healthy subjects, even a decreased sensitivity to sensory stimuli in general (Dickens et al., 2003). Focusing on tactile sensitivity and how this may also be altered in affective disorders, we have found practically no scientific literature on the subject. A recent study conducted on a sample of young women (Lehoux and Abbott, 2011) suggests that a subclinical low mood state is associated with a decrease in tactile sensitivity and a reduced response to topical capsaicin. In the mid20th century, Ey et al. (1960) described that the neurological exam in melancholic crises sometimes showed decreased reflexes, muscular hypotonia and hypoesthesia. References exist in other classic texts that suggest not just a decrease in tactile sensitivity in either an extensive or general sense, but localized hypoesthesia. López-Ibor (1950) described that acroparesthesia, a sensory disorder of the distal parts of the extremities defined in neurological works as a disorder that is an independent entity, usually included among the vasomotor trophic diseases, is actually a phasic symptom of the affective spectrum. In addition, he explained that the genesis of this disorder must be central and not peripheral, as its distribution is not metameric but rather corresponds with the distribution of thalamic anesthetics. Rojo-Sierra (1980) defined functional hypoesthesia as that which is not due to an organic injury but that obeys affective dynamisms or alterations of the conscience. He suggests that its biopsychic substrate is found in the thalamus, because as the neurologist Otfrid Foerster (1935) demonstrated, many thalamic disorders, in addition to being
129
accompanied by affective alterations, produce hypoesthesia centered on the malleolar regions of the foot. In addition, Rojo-Sierra (1980) demonstrated that subjects with symptoms of anxiety or depression presented differences in sensitivity between the internal and external malleolar regions of each foot, a difference that disappears when the anguish is alleviated. Therefore, the reason we have centered our study around sensitivity in this anatomical area specifically is based on our experience accumulated through the systematic neurological examination of ambulatory patients during decades. Specifically, in this study we have explored tactile sensitivity in depressed patients in order to test the findings of the authors cited above, that is, the presence of tactile hypoesthesia in one of the malleoli compared to its contralateral counterpart.
2. Method 2.1. Participants Eighty-six patients in a depressive state took part in the experiment. All patients were recruited from an outpatient unit at the Psychiatry Department at the “Hospital Universitario y Politécnico La Fe” (Valencia, Spain). An additional control group of 101 healthy individuals was recruited through advertising in the community. Demographic and clinical details are presented in Table 1. This study was authorized by the ethics committee from the “Health Research Institute La Fe” and all participants gave written informed consent before participating. Participants were excluded depending on the following criteria: neurological history and/or other psychiatric diagnoses based on ICD-10 criteria. Patients fulfilled the ICD-10 criteria for a depressive episode (F32) or mixed anxiety-depressive disorder (F41.42) at the time of assessment. Clinical interview and case note review were used for establishing the diagnoses. ICD-10 diagnoses were corroborated by the psychiatrist in charge and by a postgraduate psychiatric intern. In order to assess the affective and anxiety symptoms in both groups, two clinical scales were applied: the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1980) and the State-Trait Anxiety Inventory (STAI; Spielberger et al., 1983). 2.2. Procedure After signing an informed consent form, all participants responded to a demographic and clinic interview and to the HRSD and STAI. As part of a Neurological Clinical Examination, patients were examined using the Wartenberg wheel, a medical device for neurological use, in order to determine the presence of hypoesthesia on both sides of their ankles. Doctors with experience in neurological examination and unaware of our study's hypothesis explored the differences in tactile sensitivity between both superior limbs and between both inferior limbs, with the patient in a seated position. Wartenberg wheel was used on both ankle malleoli, internal and external, in order to determine the presence Table 1 Demographic and clinical data from control group and depressed group. Data shown are averages and standard deviations.
% Female Age HRSD STAI
Control (N ¼ 101)
Depressed (N ¼ 86)
p
44.6 39.1 (16.2) 3.2 (3.9) 15.5 (9.6)
61.4 49.5 (13.7) 15.8 (6.7) 39.3 (12.7)
.03 .00 .00 .00
Note: The p values correspond to the omnibus test for all groups.
130
L. Livianos et al. / Journal of Affective Disorders 171 (2015) 128–131
Table 2 Crosstab of the neurological outcome vs. groups (depressive patients and healthy controls).
Hypoesthesia Malleoli Total
Yes No
Patients
Controls
Total
61 22 83
28 75 103
89 97 186
of tactile hypoesthesia. Participants were instructed to identify whether the sensation was the same on one side as the other. The presence of unequal sensitivity between the malleoli of one ankle was classified as hypoesthesia. 2.3. Data analysis A chi-square test was employed to compare the differences between the groups, that is, depressed patients and healthy individuals. Afterward, a Student's t-test was performed to test whether there were differences in anxiety and depression scores as a function of whether or not the participants presented malleolar hypoesthesia.
3. Results To examine whether depressed patients and healthy individuals differed in the presence of hypoesthesia, we conducted the chi-square test. The chi-square test revealed a significant effect, χ2(1) ¼39.50, p o.001. The mean indicates that depressed group has higher percentage of hypoesthesia than control group (73.5% vs. 27.2%, respectively). See Table 2 for a crosstab of the skin test vs. the patients/control group. In addition, binary classification data are calculated, Sensitivity is 73.5% (95% CI: 62.66% to 82.58%), Specificity 72.8% (95% CI: 63.16% to 81.11%), Positive Predictive Value (PPV) 68.5% (95% CI: 57.83% to 77.97%) and Negative Predictive Value (NPV) 77.32% (95% CI: 67.70% to 85.20%). In addition, to examine whether participants with hypoesthesia vs. participants without hypoesthesia showed differences on depression scores and anxiety scores, we conducted the t Student's Test. The t test revealed a significant effect for depression, t(183)¼5.66, po.001, and a significant effect for anxiety, t(183)¼5.08, po.001. Participants with hypoesthesia had higher depression scores than participants without hypoestesia (M¼ 12.11, SD¼7.99, and M¼5.76, SD¼ 7.27, respectively). Participants with hypoesthesia also showed higher anxiety scores than participants without hypoestesia (M¼32.08, SD¼16.13, and M¼20.60, SD¼14.38, respectively).
both feet. However, though this study has not tested whether the substrate of this hypoesthesia resides in the thalamus, neuroimaging studies have found that patients with depression present anomalies both on a structural and a functional level in this area of the brain (Greicius et al., 2007). A recent meta-analysis (Bora et al., 2012) concluded that, on a structural level, individuals with greater depression have a cortico-striatal-pallidal-thalamic circuit of abnormal volume; smaller volumes were found in patients with a long history of depression and the most significant differences were found on the thalamic level. On a functional level, hypermetabolism and increased activity in the thalamic and cingulate regions have been found, reflecting a functional connectivity disorder on the neural network level. Future studies should move towards examining the possible causal link between tactile sensitivity and thalamic innervation in patients with a depressive disorder. This study comes with certain limitations that are typical in studies with patients. All patients in this study were taking psychotropic medication. Nevertheless, to our knowledge, there are no studies that have associated medication (i.e., anxiolytics and antidepressants) with skin sensitivity. As is usual, the categorization of hypoesthesia is based on patient subjectivity. Furthermore, several psychiatrists were involved in the testing, and they could have employed different criteria for determining hypoesthesia. However, the psychiatrists were not aware of the hypothesis of the study. As one reviewer point out, it would be interesting studying the sensibility in this area by additional methods such as EMG in future research. To sum up, neurological soft signs are associated with affective disorders such as depression. Both patients with specific depressive disorders and individuals who present anxiety-depressive symptomatology generally present anomalies in tactile sensitivity in their lower limbs. The detection of malleolar hypoesthesia in patients with depressive symptomatology can provide us with valuable information that could help both the diagnostic process and patient therapy. The observation of these minor signs is easily accessible using a simple neurological examination, and it could provide our medical field with a powerful tool that could provide objective information on affective disorders. Future studies should examine whether this minor neurological sign disappears or, contrarily, whether it remains fixed in individuals that no longer present symptomatology. This way, we can identify whether these signs are a characteristic state of the depressive episode, or, alternatively, this is more of a risk factor for affective disorders.
Role of funding source Nothing declared.
Conflict of interest No conflict declared.
4. Discussion Our study revealed that patients with depression are generally more likely to present malleolar hypoesthesia than participants with no pathology. We were also able to demonstrate that the participants who presented malleolar hypoesthesia presented greater depressive symptomatology as well as greater anxiety symptomatology at the time of assessment. Taken together, these findings corroborate that localized tactile sensitivity is altered in depression and correlates with anxiety-depressive symptomatology, even on a subclinical level. Our results corroborate the hypotheses proposed by López-Ibor (1950) and Rojo-Sierra (1980), that people with “anguish”, whom we have quantified by the presence of depressive and anxiety-depressive symptomatology, show hypoesthesia consisting of differences in sensitivity between the internal and external malleolar regions of
Acknowledgments We thank all of the participants without whom this study would not have been possible.
References Arnone, D., McIntosh, A.M., Ebmeier, K.P., Munafò, M.R., Anderson, I.M., 2012. Magnetic resonance imaging studies in unipolar depression: systematic review and meta-regression analyses. Eur. Neuropsychopharmacol. 22 (1), 1–16. Atanasova, B., Graux, J., El Hage, W., Hommet, C., Camus, V., Belzung, C., 2008. Olfaction: a potential cognitive marker of psychiatric disorders. Neurosci. Biobehav. Rev. 32, 1315–1325. Bleuler, E., 1916. Lehrbuch der Psychiatrie. Springer-Verlag, Berlin. Bora, E., Harrison, B.J., Davey, C.G., Yücel, M., Pantelis, C., 2012. Meta-analysis of volumetric abnormalities in cortico-striatal-pallidal-thalamic circuits in major depressive disorder. Psychol. Med. 42 (04), 671–681.
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Bubl, E., Kern, E., Ebert, D., Bach, M., Tebartz van Elst, L., 2010. Seeing gray when feeling blue? Depression can be measured in the eye of the diseased. Biol. Psychiatry 68 (2), 205–208. Carroll, B.J., 1985. Dexamethasone suppression test: a review of contemporary confusion. J. Clin. Psychiatry 46, 13–24. Caruncho, H.J., Rivera-Baltanás, T., 2010. Biomarkers of depression. Rev. Neurol. 50 (8), 470–476. Dickens, C., McGowan, L., Dale, S., 2003. Impact of depression on experimental pain perception: a systematic review of the literature with meta-analysis. Psychosom. Med. 65, 369–375. Diener, C., Kuehner, C., Brusniak, W., Ubl, B., Wessa, M., Flor, H., 2012. A metaanalysis of neurofunctional imaging studies of emotion and cognition in major depression. Neuroimage 61 (3), 677–685. Ey, H., Bernard, P., Brisset, C., 1960. Manuel de Psychiatrie. Masson, Paris. Foerster, O., 1935. Handbuch der Neurologie: Anatomie, Vol. 1. Springer, Berlin. Greicius, M.D., Flores, B.H., Menon, V., Glover, G.H., Solvason, H.B., Kenna, H., Schatzberg, A.F., 2007. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol. Psychiatry 62 (5), 429–437. Gupta, R.K., Kumar, R., Kasper, S., 2002. Physical signs in psychiatry: a step towards evidence-based medicine. Int. J. Psychiatry Clin. Pract. 6, 69–72. Hamilton, M., 1980. Rating depressive patients. J. Clin. Psychiatry 41, 21–24. Krebs, M.O., Mouchet, S., 2007. Neurological soft signs and schizophrenia: a review of current knowledge. Rev. Neurol. 163 (12), 1157–1168. Lehoux, C.P., Abbott, F.V., 2011. Pain, sensory function and neurogenic inflammatory response in young women with low mood. J. Psychosom. Res. 70 (3), 241–249. López-Ibor, J.J., 1950. La angustia vital. Paz Montalvo, Madrid.
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Mayberg, H.S., Brannan, S.K., Mahurin, R.K., Jerabek, P.A., Brickman, J.S., Tekell, J.L., Silva, J.A., McGinnis, S., Glass, T.G., Martin, C.C., Fox, P.T., 2012. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 8 (4), 1057–1061. Miller, A.H., Maletic, V., Raison, C.L., 2009. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741. Rojo-Sierra, M., 1980. Psicología y Psicopatología de la Percepción, Memoria y Fantasía. Eunibar, Barcelona. Rush, A.J., Giles, D.E., Schlesser, M.A., Orsulak, P.J., Weissenburger, J.E., Fulton, C.L., Fairchild, C.J., Roffwarg, H.P., 1997. Dexamethasone response, thyrotropinreleasing hormone stimulation, rapide eye movement latency, and subtypes of depression. Biol. Psychiatry 41 (9), 915–928. Sadock, B.J., Kaplan, H.I., Sadock, V.A., 2007. Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Lippincott Williams & Wilkins, Philadelphia, PA. Schmidt, H.D., Shelton, R.C., Duman, R.S., 2011. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 36 (12), 2375–2394. Spielberger, C.D., Gorsuch, R.L., Lushene, P.R., Vagg, P.R., Jacobs, G.A., 1983. Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press, Palo Alto, CA. Steiger, A., Kimura, M., 2010. Wake and sleep EEG provide biomarkers in depression. J. Psychiatr. Res. 44 (4), 242–252. World Health Organisation, 1992. ICD-10 Classifications of Mental and Behavioural Disorder: Clinical Descriptions and Diagnostic Guidelines. World Health Organisation, Geneva.
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Brief report
Hypoesthesia of the malleolus as a soft sign in depression Lorenzo Livianos a,b,c, Pablo I. González-Valls a, Ana C. García-Blanco a,n, Helena Tobella a, Ignacio Díaz-Alonso a, Núria Alberola a, Susana García-Aznar a, Ramón Bellot a, Vanessa Saiz a, Lourdes Ros a a
Department of Psychiatry, La Fe University and Polytechnic Hospital, 46010 Valencia, Spain University of Valencia, Department of Medicine, Valencia, Spain c CIBERESP, Spain b
art ic l e i nf o
a b s t r a c t
Article history: Received 15 June 2014 Received in revised form 15 September 2014 Accepted 20 September 2014 Available online 30 September 2014
Background: Physical signs often are present in many psychiatric conditions, making up a fundamental part of them and accompanying the psychiatric manifestations themselves. Identifying minor neurological signs is especially of interest due to they are easily accessible through simple neurological examination and could be a useful if underused tool for the diagnostic process and patient therapy. Method: A group of depressed patients (n ¼ 85) and group of healthy individuals (n ¼101) that served as control were examined using the Wartenberg wheel, a medical device for neurological use, in order to determine the presence of hypoesthesia on both sides of their ankles. Results: The data revealed: i) patients with depression are generally more likely to present malleolar hypoesthesia than healthy participants; and ii) participants who presented malleolar hypoesthesia presented greater depressive symptomatology as well as greater anxiety symptomatology at the time of assessment. Limitations: Although all patients in this study were taking psychotropic medication, anxiolytics and antidepressants are not associated with skin sensitivity. As is usual, the categorization of hypoesthesia is based on participant subjectivity. However, this subjectivity cannot explain the differences between depressed patients and healthy individuals. Conclusions: The present findings corroborate that localized tactile sensitivity is altered in depression and correlates with anxiety-depressive symptomatology, even on a subclinical level. The observation of neurological soft signs such as the detection of malleolar hypoesthesia in patients with depressive symptomatology is easily accessible using a simple neurological examination, and it could became a powerful tool that could provide objective information on affective disorders. & 2014 Published by Elsevier B.V.
Keywords: Depression Neurological soft signs Tactile sensitivity Hypoesthesia
1. Introduction The lack of objective diagnostic tests has traditionally been one of psychiatry's main disadvantages compared to other fields of medicine. However, mental illness is ocassionally inseparable from certain physical signs, and therefore, identifying them could be a useful if underused tool for the diagnostic process. In the case of minor neurological signs, although they may be aspecific, they are easily accessible through simple procedures. However, as Gupta et al. (2002) point out, the current diagnostic manuals, such as the ICD-10 (World Health Organisation, 1992), have not
n
Corresponding author. Tel.: þ 34 961 245553. E-mail address: [email protected] (A.C. García-Blanco).
http://dx.doi.org/10.1016/j.jad.2014.09.034 0165-0327/& 2014 Published by Elsevier B.V.
sufficiently addressed the presence of physical signs, particularly in depressive disorders and anxiety disorders. Actually, in the study of affective disorders there have been numerous findings in the literature concerning physical signs or biomarkers; from Otto Veraguth's 1935 description of the wellknown palpebral fold (Sadock et al., 2007) to the most current discoveries in the field of neuroimaging (see Diener et al. (2012), for a review). Depression has been associated with different measurable biomarkers in the laboratory related to the hypothalamic–pituitary–adrenocortical axis (see Carroll (1985), for dexamethasone suppression; see Rush et al. (1997), for reduced TRH; see Steiger and Kimura (2010), for sleep alterations—which would be regulated by this axis). Other endocrine parameters have also been analyzed, such as insulin resistance (Schmidt et al., 2011), sex steroids, GH, melatonin or prolactin (Sadock et al., 2007), although with inconsistent results. Metabolic markers such as a decrease in
L. Livianos et al. / Journal of Affective Disorders 171 (2015) 128–131
serotonin transporter, hypocholesterolemia and a decrease in the phosphorylation of the CREB protein (Caruncho and RiveraBaltanás, 2010). Another recent area of interest in depression is that of inflammation and its cytokines (Miller et al., 2009). In the field of neuroimaging, more relevant findings relative to greater levels of depression have been discovered in: ii) structural neuroimaging (subcortical hyperintensities in periventricular regions, the basal ganglia and the thalamus, as well as reductions in the volume of the frontal lobes, hippocampus and basal ganglia; Arnone et al., 2012); and ii) functional neuroimaging (hypometabolism in dorsolateral prefrontal area, anterior cingulate cortex and the temporal lobes; Mayberg et al., 2012). All of the biological signs listed here have been of significant importance up until now in the field of research, but not in common clinical practice. This is due to several factors: i) laboratory and neuroimaging techniques are expensive tests that cannot be used as everyday diagnostic tests; and ii) the results are not completely consistent. Therefore, the analysis of minor neurological signs is especially of interest. The observation of these signs does not require sophisticated methods; neurological examination is a basic tool in medicine, and it can provide objective information on the underlying illness. Though it is true that in the scientific literature there exist many studies on schizophrenia that have associated it with different minor neurological signs (Krebs and Mouchet, 2007), we know little about their relationship with affective disorders. This line of research on depression has provided particularly interesting data relative to pain and sensory perception. Bleuler (1916) described alterations of the senses in neurotic and melancholic states such as hyperesthesia and hyper-, hypo- and analgesia. Over the last few years, research has been conducted that has demonstrated objective alterations of the senses in depressed patients. Recent studies have found a reduction of the perception of contrast measured via electroretinogram in these patients that correlated with the severity of the depression (Bubl et al., 2010). Olfactory capacity has also been evaluated and alterations have also been detected in the sensitivity and identification of odors (Atanasova et al., 2008). As for the relationship between depression and pain, several studies indicate that the perception of painful stimuli has a higher threshold in depressed subjects than in healthy subjects, even a decreased sensitivity to sensory stimuli in general (Dickens et al., 2003). Focusing on tactile sensitivity and how this may also be altered in affective disorders, we have found practically no scientific literature on the subject. A recent study conducted on a sample of young women (Lehoux and Abbott, 2011) suggests that a subclinical low mood state is associated with a decrease in tactile sensitivity and a reduced response to topical capsaicin. In the mid20th century, Ey et al. (1960) described that the neurological exam in melancholic crises sometimes showed decreased reflexes, muscular hypotonia and hypoesthesia. References exist in other classic texts that suggest not just a decrease in tactile sensitivity in either an extensive or general sense, but localized hypoesthesia. López-Ibor (1950) described that acroparesthesia, a sensory disorder of the distal parts of the extremities defined in neurological works as a disorder that is an independent entity, usually included among the vasomotor trophic diseases, is actually a phasic symptom of the affective spectrum. In addition, he explained that the genesis of this disorder must be central and not peripheral, as its distribution is not metameric but rather corresponds with the distribution of thalamic anesthetics. Rojo-Sierra (1980) defined functional hypoesthesia as that which is not due to an organic injury but that obeys affective dynamisms or alterations of the conscience. He suggests that its biopsychic substrate is found in the thalamus, because as the neurologist Otfrid Foerster (1935) demonstrated, many thalamic disorders, in addition to being
129
accompanied by affective alterations, produce hypoesthesia centered on the malleolar regions of the foot. In addition, Rojo-Sierra (1980) demonstrated that subjects with symptoms of anxiety or depression presented differences in sensitivity between the internal and external malleolar regions of each foot, a difference that disappears when the anguish is alleviated. Therefore, the reason we have centered our study around sensitivity in this anatomical area specifically is based on our experience accumulated through the systematic neurological examination of ambulatory patients during decades. Specifically, in this study we have explored tactile sensitivity in depressed patients in order to test the findings of the authors cited above, that is, the presence of tactile hypoesthesia in one of the malleoli compared to its contralateral counterpart.
2. Method 2.1. Participants Eighty-six patients in a depressive state took part in the experiment. All patients were recruited from an outpatient unit at the Psychiatry Department at the “Hospital Universitario y Politécnico La Fe” (Valencia, Spain). An additional control group of 101 healthy individuals was recruited through advertising in the community. Demographic and clinical details are presented in Table 1. This study was authorized by the ethics committee from the “Health Research Institute La Fe” and all participants gave written informed consent before participating. Participants were excluded depending on the following criteria: neurological history and/or other psychiatric diagnoses based on ICD-10 criteria. Patients fulfilled the ICD-10 criteria for a depressive episode (F32) or mixed anxiety-depressive disorder (F41.42) at the time of assessment. Clinical interview and case note review were used for establishing the diagnoses. ICD-10 diagnoses were corroborated by the psychiatrist in charge and by a postgraduate psychiatric intern. In order to assess the affective and anxiety symptoms in both groups, two clinical scales were applied: the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1980) and the State-Trait Anxiety Inventory (STAI; Spielberger et al., 1983). 2.2. Procedure After signing an informed consent form, all participants responded to a demographic and clinic interview and to the HRSD and STAI. As part of a Neurological Clinical Examination, patients were examined using the Wartenberg wheel, a medical device for neurological use, in order to determine the presence of hypoesthesia on both sides of their ankles. Doctors with experience in neurological examination and unaware of our study's hypothesis explored the differences in tactile sensitivity between both superior limbs and between both inferior limbs, with the patient in a seated position. Wartenberg wheel was used on both ankle malleoli, internal and external, in order to determine the presence Table 1 Demographic and clinical data from control group and depressed group. Data shown are averages and standard deviations.
% Female Age HRSD STAI
Control (N ¼ 101)
Depressed (N ¼ 86)
p
44.6 39.1 (16.2) 3.2 (3.9) 15.5 (9.6)
61.4 49.5 (13.7) 15.8 (6.7) 39.3 (12.7)
.03 .00 .00 .00
Note: The p values correspond to the omnibus test for all groups.
130
L. Livianos et al. / Journal of Affective Disorders 171 (2015) 128–131
Table 2 Crosstab of the neurological outcome vs. groups (depressive patients and healthy controls).
Hypoesthesia Malleoli Total
Yes No
Patients
Controls
Total
61 22 83
28 75 103
89 97 186
of tactile hypoesthesia. Participants were instructed to identify whether the sensation was the same on one side as the other. The presence of unequal sensitivity between the malleoli of one ankle was classified as hypoesthesia. 2.3. Data analysis A chi-square test was employed to compare the differences between the groups, that is, depressed patients and healthy individuals. Afterward, a Student's t-test was performed to test whether there were differences in anxiety and depression scores as a function of whether or not the participants presented malleolar hypoesthesia.
3. Results To examine whether depressed patients and healthy individuals differed in the presence of hypoesthesia, we conducted the chi-square test. The chi-square test revealed a significant effect, χ2(1) ¼39.50, p o.001. The mean indicates that depressed group has higher percentage of hypoesthesia than control group (73.5% vs. 27.2%, respectively). See Table 2 for a crosstab of the skin test vs. the patients/control group. In addition, binary classification data are calculated, Sensitivity is 73.5% (95% CI: 62.66% to 82.58%), Specificity 72.8% (95% CI: 63.16% to 81.11%), Positive Predictive Value (PPV) 68.5% (95% CI: 57.83% to 77.97%) and Negative Predictive Value (NPV) 77.32% (95% CI: 67.70% to 85.20%). In addition, to examine whether participants with hypoesthesia vs. participants without hypoesthesia showed differences on depression scores and anxiety scores, we conducted the t Student's Test. The t test revealed a significant effect for depression, t(183)¼5.66, po.001, and a significant effect for anxiety, t(183)¼5.08, po.001. Participants with hypoesthesia had higher depression scores than participants without hypoestesia (M¼ 12.11, SD¼7.99, and M¼5.76, SD¼ 7.27, respectively). Participants with hypoesthesia also showed higher anxiety scores than participants without hypoestesia (M¼32.08, SD¼16.13, and M¼20.60, SD¼14.38, respectively).
both feet. However, though this study has not tested whether the substrate of this hypoesthesia resides in the thalamus, neuroimaging studies have found that patients with depression present anomalies both on a structural and a functional level in this area of the brain (Greicius et al., 2007). A recent meta-analysis (Bora et al., 2012) concluded that, on a structural level, individuals with greater depression have a cortico-striatal-pallidal-thalamic circuit of abnormal volume; smaller volumes were found in patients with a long history of depression and the most significant differences were found on the thalamic level. On a functional level, hypermetabolism and increased activity in the thalamic and cingulate regions have been found, reflecting a functional connectivity disorder on the neural network level. Future studies should move towards examining the possible causal link between tactile sensitivity and thalamic innervation in patients with a depressive disorder. This study comes with certain limitations that are typical in studies with patients. All patients in this study were taking psychotropic medication. Nevertheless, to our knowledge, there are no studies that have associated medication (i.e., anxiolytics and antidepressants) with skin sensitivity. As is usual, the categorization of hypoesthesia is based on patient subjectivity. Furthermore, several psychiatrists were involved in the testing, and they could have employed different criteria for determining hypoesthesia. However, the psychiatrists were not aware of the hypothesis of the study. As one reviewer point out, it would be interesting studying the sensibility in this area by additional methods such as EMG in future research. To sum up, neurological soft signs are associated with affective disorders such as depression. Both patients with specific depressive disorders and individuals who present anxiety-depressive symptomatology generally present anomalies in tactile sensitivity in their lower limbs. The detection of malleolar hypoesthesia in patients with depressive symptomatology can provide us with valuable information that could help both the diagnostic process and patient therapy. The observation of these minor signs is easily accessible using a simple neurological examination, and it could provide our medical field with a powerful tool that could provide objective information on affective disorders. Future studies should examine whether this minor neurological sign disappears or, contrarily, whether it remains fixed in individuals that no longer present symptomatology. This way, we can identify whether these signs are a characteristic state of the depressive episode, or, alternatively, this is more of a risk factor for affective disorders.
Role of funding source Nothing declared.
Conflict of interest No conflict declared.
4. Discussion Our study revealed that patients with depression are generally more likely to present malleolar hypoesthesia than participants with no pathology. We were also able to demonstrate that the participants who presented malleolar hypoesthesia presented greater depressive symptomatology as well as greater anxiety symptomatology at the time of assessment. Taken together, these findings corroborate that localized tactile sensitivity is altered in depression and correlates with anxiety-depressive symptomatology, even on a subclinical level. Our results corroborate the hypotheses proposed by López-Ibor (1950) and Rojo-Sierra (1980), that people with “anguish”, whom we have quantified by the presence of depressive and anxiety-depressive symptomatology, show hypoesthesia consisting of differences in sensitivity between the internal and external malleolar regions of
Acknowledgments We thank all of the participants without whom this study would not have been possible.
References Arnone, D., McIntosh, A.M., Ebmeier, K.P., Munafò, M.R., Anderson, I.M., 2012. Magnetic resonance imaging studies in unipolar depression: systematic review and meta-regression analyses. Eur. Neuropsychopharmacol. 22 (1), 1–16. Atanasova, B., Graux, J., El Hage, W., Hommet, C., Camus, V., Belzung, C., 2008. Olfaction: a potential cognitive marker of psychiatric disorders. Neurosci. Biobehav. Rev. 32, 1315–1325. Bleuler, E., 1916. Lehrbuch der Psychiatrie. Springer-Verlag, Berlin. Bora, E., Harrison, B.J., Davey, C.G., Yücel, M., Pantelis, C., 2012. Meta-analysis of volumetric abnormalities in cortico-striatal-pallidal-thalamic circuits in major depressive disorder. Psychol. Med. 42 (04), 671–681.
L. Livianos et al. / Journal of Affective Disorders 171 (2015) 128–131
Bubl, E., Kern, E., Ebert, D., Bach, M., Tebartz van Elst, L., 2010. Seeing gray when feeling blue? Depression can be measured in the eye of the diseased. Biol. Psychiatry 68 (2), 205–208. Carroll, B.J., 1985. Dexamethasone suppression test: a review of contemporary confusion. J. Clin. Psychiatry 46, 13–24. Caruncho, H.J., Rivera-Baltanás, T., 2010. Biomarkers of depression. Rev. Neurol. 50 (8), 470–476. Dickens, C., McGowan, L., Dale, S., 2003. Impact of depression on experimental pain perception: a systematic review of the literature with meta-analysis. Psychosom. Med. 65, 369–375. Diener, C., Kuehner, C., Brusniak, W., Ubl, B., Wessa, M., Flor, H., 2012. A metaanalysis of neurofunctional imaging studies of emotion and cognition in major depression. Neuroimage 61 (3), 677–685. Ey, H., Bernard, P., Brisset, C., 1960. Manuel de Psychiatrie. Masson, Paris. Foerster, O., 1935. Handbuch der Neurologie: Anatomie, Vol. 1. Springer, Berlin. Greicius, M.D., Flores, B.H., Menon, V., Glover, G.H., Solvason, H.B., Kenna, H., Schatzberg, A.F., 2007. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol. Psychiatry 62 (5), 429–437. Gupta, R.K., Kumar, R., Kasper, S., 2002. Physical signs in psychiatry: a step towards evidence-based medicine. Int. J. Psychiatry Clin. Pract. 6, 69–72. Hamilton, M., 1980. Rating depressive patients. J. Clin. Psychiatry 41, 21–24. Krebs, M.O., Mouchet, S., 2007. Neurological soft signs and schizophrenia: a review of current knowledge. Rev. Neurol. 163 (12), 1157–1168. Lehoux, C.P., Abbott, F.V., 2011. Pain, sensory function and neurogenic inflammatory response in young women with low mood. J. Psychosom. Res. 70 (3), 241–249. López-Ibor, J.J., 1950. La angustia vital. Paz Montalvo, Madrid.
131
Mayberg, H.S., Brannan, S.K., Mahurin, R.K., Jerabek, P.A., Brickman, J.S., Tekell, J.L., Silva, J.A., McGinnis, S., Glass, T.G., Martin, C.C., Fox, P.T., 2012. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 8 (4), 1057–1061. Miller, A.H., Maletic, V., Raison, C.L., 2009. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741. Rojo-Sierra, M., 1980. Psicología y Psicopatología de la Percepción, Memoria y Fantasía. Eunibar, Barcelona. Rush, A.J., Giles, D.E., Schlesser, M.A., Orsulak, P.J., Weissenburger, J.E., Fulton, C.L., Fairchild, C.J., Roffwarg, H.P., 1997. Dexamethasone response, thyrotropinreleasing hormone stimulation, rapide eye movement latency, and subtypes of depression. Biol. Psychiatry 41 (9), 915–928. Sadock, B.J., Kaplan, H.I., Sadock, V.A., 2007. Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Lippincott Williams & Wilkins, Philadelphia, PA. Schmidt, H.D., Shelton, R.C., Duman, R.S., 2011. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 36 (12), 2375–2394. Spielberger, C.D., Gorsuch, R.L., Lushene, P.R., Vagg, P.R., Jacobs, G.A., 1983. Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press, Palo Alto, CA. Steiger, A., Kimura, M., 2010. Wake and sleep EEG provide biomarkers in depression. J. Psychiatr. Res. 44 (4), 242–252. World Health Organisation, 1992. ICD-10 Classifications of Mental and Behavioural Disorder: Clinical Descriptions and Diagnostic Guidelines. World Health Organisation, Geneva.