METHOD AND APPARATUS FOR MEASUREMENT OF PSYCHOLOGICAL PAIN AS A CONSTRUCT FOR DIAGNOSIS, TREATMENT, AND DRUG

DEVELOPMENT

CROSS REFERENCE TO RELATED APPLtCATIONS

[0001] The present invention claims priority under 35 U.S.C. 119{e) from provisional application Ser. No. 60/741 ,027, filed on November 30, 2005 and entitled "Method and Apparatus for Measurement of Psychological Pain as a Construct for Diagnosis, Treatment, and Drug Development ¹¹ , the entire disclosure of which is herein incorporated by reference.

BACKGROUND OF THE INVENTION

1. FIELD OF THE INVENTION

|0002] The present invention relates to apparatus and a method generally useful in quantitatively measuring levels of psychological pain experienced by a human subject. The invention relates more particularly, but not by way of limitation, to scales and a method for characterizing ifte level of psychological pain of a subject based on measured parameters of psychological pain, and for using such measurements to quantitatively: categorize the subject's pain, to assess the outcome of the subject in response to therapeutic interventions, and to enable the development of pharmaceutical compounds and/or medical devices to treat such psychological pain.

2. DESCRIPTION OF THE RELATED ART

[0003] Healthcare providers are continually faced with the problems of diagnosing and treating patients suffering from varying levels and types of pain. Difficulty in properly diagnosing and treating physical pain often results in

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ineffective treatments. In the realm of mental, or psychological, pain these problems are even more dramatic. In physical pain numerous attempts have been made to produce objective measurement scales, and such efforts have met with significant success, in mental pain, no such scales or successes have been developed prior to the conception and development thereof by the instant inventors.

[0Q04J Psychological pain, although referred to in scientific and literary publications, has not been measured with rigorous scientific methodology nor has it been proposed as a construct for the development of pharmaceutical agents to treat it and/or related disorders. Psychological pain is reported by a subgroup of mood disorder patients to be equal to or more painful than physical pain. The psychological pain of severe depression is often perceived as worse than any physical pain that the person has experienced and may be a critical component of suiddality, and other outcomes, that need to be systematically assessed in patients.

[0005] Neuroimaging data shows regional activation of brain structures that are common to both physical pain and psychological pain. The objective assessment of psychological pain will enable a skilled practitioner to create new drug targets and medical device interventions specific for the treatment of psychological, and other forms of, pain. The inventors have found that a subgroup of compounds with antidepressant activity are effective in the treatment of psychological pain as disclosed in co-pending application Ser. No. 60/ — , — , filed on August 11 , 2006 and entitled "Composition for Treating Psychological Pain and Pharmacological Method of Treating Acute and Chronic Psychological Pain Including a Combination Drug Therapy", the disclosure of which is incorporated herein by reference in its entirety. Psychological pain is prominent in many psychiatric illnesses including major depressive disorder, bipolar and schizophrenia and many other psychiatric and physical disorders. Unbearable psychological pain is a common reason for suicide listed in suicide notes from individuals who kill themselves. IQQQ&1 Very few attempts to objectively measure psychological pain

have been attempted to date. One method, the Orbach scale, hereinafter "OMMP", mentions in name the symptom of psychological pain, and suggests a connection to suicidality. It, however, reflects different origins from the instant invention, the "Mee-Bunney Scale", hereinafter known as "MBS". [0007] The OMMP scale is not as readily quantifiable as the scale of the instant invention and surveys multiple psychological spheres of the pain experience rather than focusing on measuring psychological pain itself. The questions listed in the Orbach scale are less pain specific than those found in the MBS. For example, the OMMP has a broad focus, based on nine factors including irreversibility, loss of control, narcissistic wounds, emotional flooding, freezing, self-estrangement, confusion, social distancing, and emptiness. The OMMP scale does include two 'pain' questions: "The pain will never go away" and "I will never be able to reduce the pain". However, these questions are categorized under "irreversibility" rather than a direct measure of mental pain. Although the investigators imply in the discussion of the scale "mental pain is a distinguishable subjective experience", they fail to formally separate items of psychological pain ("the OMMP scale provides a wide, multifaceted picture of inter-related complexities that make up the experience of mental pain to provide a 'feel' for one's subjective experience") from measures of other psychological disorders. In publications regarding the OMMP, the scale was, because of the limitations mentioned above, never suggested to be useful in the development of therapeutics to treat psychological pain.

[0008] Previous work in the area of psychological pain has not proposed using the quantification of psychological pain for the development of pharmaceutical agents to treat it. Additionally, the prior art does not disclose an objective way to measure and monitor this form of pain. The objective methods disclosed herein will serve as the first process to develop and qualify potential therapeutic interventions for psychological, and related, forms of pain. [0009] The observation that psychological pain can evoke what appears to be physical pain 'responses' may underlie some of the discomfort associated with psychological pain. It is recognized that chronic pain, depression and

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psychological pain are interactive complex multidimensional syndromes that have the capacity to influence one another. The recognition of psychological pain as a construct could well provide important information concerning the risk for suicide and other outcomes. The measurement of psychological pain will further help target novel compounds and/or devices for the treatment of varied pain- related symptoms.

[0010] Finally, it is also envisioned that the measurement of psychological pain will be useful across non-patient subject populations such as the military, select work forces, and other organizations wherein quantification of psychological pain would be beneficial.

SUMMARY QF THE INVENTION

[0011] The instant invention comprises methods and tools for providing a multidimensional indication of mental pain being experienced by a person that includes muftiple selection indicators, each being indicative of variations of a respective dimension of mental pain. A method of measuring psychological pain in accordance with the invention includes the steps of providing a scale indicative of mental pain being experienced by a person and using it to assess the level of mental pain experienced by a subject. The scale may be so used before, during and after treatment. The method further includes using the output to recommend therapeutic regimes for the patient. The method also includes using the output to assess the effectiveness of a given therapeutic regime on a patient, or population of patients such as found in clinical trials. Additionally, the method is designed to enable drug and/or device development efforts to treat psychological, and other forms of, pain. Finally, the method includes screening subject populations such as the military, select work forces, and other organizations wherein quantification of psychological pain would be beneficial.

[0012] Sn accordance with another aspect of the invention, a scale for measuring psychological pain includes a plurality of scale items, each scale item being directed to either a measure of psychological pain intensity or to a measure of psychological pain quality.

[0013] In accordance with another aspect of the invention, a method for providing characterizations and measurements of psychological pain includes the steps of providing a scale indicative of mental pain being experienced by a person, and using the scale in the diagnosis, treatment, and therapeutic development of pharmaceutical compounds to treat psychological, and other forms of, pain.

[0014] In accordance with yet another aspect of the invention, a method of screening a subject includes a step of assessing psychological pain experienced by a subject via the use of a psychological pain scale and a step of providing a classification regarding the subject based upon the psychological

pain scale output.

[0015] in accordance with another aspect of the invention, a method of evaluating psychoiogical pain of a patient includes a step of assessing a level of psychological pain experienced by the patient via the use of a psychoiogical pain scale at different times during each of a plurality of sessions, a step of monitoring the level of psychological pain experienced by the patient during each of the sessions based upon the psychological pairi scale and a step of providing a determination regarding the psychological pain of the patient based upon changes observed in the psychological pain scale output. [0016] in accordance with yet another aspect of the invention, a method of evaluating effectiveness of a psychological pain treatment for a patient includes a step of assessing a level of psychological pain experienced by a patient via the use of a psychological pain scale at different times during each of a plurality of sessions, a step of monitoring the level of psychological pain experienced by the patient during each of the sessions based upon a psychological pain scale and a step of providing a determination regarding psychological pain relief based upon the changes observed in the psychological pain scale output

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 is a table listing patient quotes describing psychological pain;

[0018] FIG. 2 is a schematic representation showing the hypothesized contribution of chronic psychological pain, chronic physical pain and depression to increased suicidality;

[0019] FIG. 3A is a table listing brain imaging data of regional activational changes associated with psychological pain paradigms;

[0020] FIG. 3B is a table listing further brain imaging data of regional activational changes associated with psychological pain paradigms;

[0021] FiG. 3C is a table listing further brain imaging data of regional activational changes associated with psychological pain paradigms;

[0022] FIG. 4A is a table listing brain imaging data of regional activational changes associated with anticipation of simulated physical pain;

[0023] FIG. 4B is a table listing further brain imaging data of regional activational changes associated with anticipation of simulated physical pain;

[0024] FIG. 5A and FIG. 5B is a listing of the Mee-Bunney psychological pain assessment inventory quantitative scale module in accordance with the invention;

[0025] FIG. 6 is a flow chart of a method of measuring psychological pain in accordance with the invention;

[0026] FIG. 7 is a flow chart of a method for providing characterizations and measurements of psychological pain in accordance with the invention;

[0027] FIG. 8 is a flow chart of a method of screening a subject in accordance with the invention;

[0028] . FIG. 9 is a flow chart of a method of evaluating psychological pain of a patient in accordance with the invention; and

[0029] FIG. 10 is a flow chart of a method of evaluating effectiveness of a psychological pain treatment for a patient in accordance with the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

[0030] The purpose of the "Mee-Bunney Scale" in accordance with the invention is to assess the degree and time of onset of a patient's current ievei of psychological pain as a construct. Every question in the MBS questionnaire uses the word 'pain' to measure psychological pain in a manner similar to that of physical pain as shown in FlG. 5A and FlG. 5B. The MBS may include a structured interview or self-administered scale including the 20 listed items. The MBS was constructed to serve as a direct measure of psychological pain with the intention of assessing the efficacy of drugs that are specific to psychological pain, among other applications.

[0031] The MBS uses a Likert 1-5 severity parameter. Using the MBS, psychological pain may be characterized in terms of: 1 } severity; 2} frequency; 3) response to medications; 4) comparison to experienced physical pain; 5) its relationship to suicidal thoughts: and 6) whether it is precedent or antecedent to depression. The 20 items in the MBS rated on a 1-5 scale contribute to the assessment of these characterizations. The MBS encompasses items that intentionally measure psychological pain intensity (items 1-5, 8, 10, and 13-15), and psychological pain qualities including duration (item 4), location (items 16- 17), and temporal relation to depression symptoms (items 18 and 19). [0032] The MBS closely resembles physical pain scales, which have been successfully used to direct pharmaceutical development, and treatment assessment, for years. The MBS also resembles certain depression scales that have been used to direct anti-depressant pharmaceutical development. [0033] The MBS was specifically designed to treat psychological pain as a construct that can be used to more accurately allow statistical analyses to direct diagnosis, pharmaceutical development, and treatment response in contrast to the OMMP.

[0034] "I can't stand the pain any longer" - one of the most common phrases found in suicide notes (Institute of Medicine, 2002)-referring, in this case, not to physical but to psychological pain. The torment of psychological

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'pain' can be so intense, that suicide seems to be the only means of escape (Kovacs, Beck, & Weissman, 1975b; Osmond, MuIIaIy, & Bisbee, 1984; Shneiciman, 1979). Recent neuroimaging studies provide evidence that psychological pain activates many of the same brain structures as physical pain. However, few studies have directly compared responses provoked by psychologically painful stimuli with those of physically noxious stimuli. [0035] In the course of conceiving of and developing the MBS, the inventors surveyed studies that focus on psychological pain including sources such as suicide notes, physician's observations, and scientific papers in addition to brain imaging studies. Neuroimaging studies involve three categories of pain: 1) induced physical pain; 2) induced simulated physical pain; and 3) induced psychological pain. Technologies used to measure regional brain differences include positron emission tomography (PET) and functional magnetic resonance imaging (fMRl).

[0036] Converging evidence suggests that psychological pain may be a risk factor for depression and/or suicide. Jt is probable that patients have differing thresholds for psychological pain as individuals do for physical pain, so what is felt as intolerable by one patient could differ in another. This inter-individual variability is not currently being captured during assessment and treatment of conditions where psychological pain is a prominent symptom. Psychological pain can be exacerbated by chronic physical pain conditions, major depressive disorder as well as severe social stresses (e.g., loss of a child). Physical pain, psychological pain and major depression are complex multidimensional syndromes with the capacity to influence one another (Bair, Robinson, Katon, & Kroenke, 2003; Fishbain, 1999; 2002; Fishbain, Cutler, Rosomoff, & Rosomoff, 1997; Fishbain, Goldberg, Rosomoff, & Rosomoff, 1991). Chronic physical pain and psychological pain can lead to depression while depression can intensify chronic physical pain and perhaps, psychological pain. The findings from the inventor's review suggest new strategies for the study of psychological pain. Moreover, it is suggested that psychological pain, analogous to hopelessness (Joiner et a!., 2001 ; Kovacs, Beck, & Weissman, 1975a) be recognized as a

distinct symptom, separate from mood disorders, and can occur across psychiatric diagnoses.

[0037] Suicide notes provide invaluable insights into the suffering associated with intense psychological pain, it is striking that many patients, although enduring a wide-range of illnesses, describe psychological pain using remarkably similar analogies. FIG. 1 lists samples of patient quotes from unpublished sources that were collected over many years from sources including clinical and suicide notes from depressed patients. For example, quotes 100, 101 , 102, 103, and 104 are taken from the Los Angeles County Coroner's Office, 1983-84 (Leenaars, 1988). Additional descriptions of psychological pain were obtained from scientific publications. Quotes were selected only if the subjects specifically used the word pain to describe their emotional distress and suffering. These quotes were not systematically obtained but are cited for the purpose of illustrating the level of intensity of psychological pain experienced by some patients. In these cases, quotes were obtained from a subgroup of patients suffering from depression. It will be important in future studies to determine the incidence of "unbearable" psychological pain associated with psychiatric illnesses including bipolar disorder (BPD), major mood disorder (MDD) and in schizophrenia (SZ). Furthermore, it may be particularly valuable to determine whether high levels of psychological pain are important contributors to suicidal behavior, associated with or independent of, psychiatric illness. [0038] It should be noted that many quotes were not included in FIG. 1 as some subjects used synonyms for pain (e.g., physical torment, body hurts, horrible suffering, constant agony, and unbearable misery) to express the sense of being overwhelmed by uncontrolled psychological pain. As seen in FIG. 1 , the last three patients 110, 111 , and 112 directly compare their experiences of psychological pain (associated with depression) with physical pain. In each case, the patients describe psychological pain as being more severe than intense physical pain. Similar observations were made by Osmond (Osmond et a!., 1984) in a study where investigators interviewed 30 patients with depressive symptoms, ail of whom also had a history of a life-threatening physical illness or trauma

including heart attacks, cancer, serious injury and multiple surgeries. Each patient was asked which experience, physical pain or the pain of depression, he or she considered the worst and which, if forced to make a choice, he or she would rather experience again. Twenty-eight of the 30 patients stated that the psychological pain associated with depression was worse than any physical pain that they had experienced. The patients described the pain associated with depression as "deep hurt, waves of agony beyond understanding, and a powerful and unshared misery"(Osmond et ai. ₍ 1984).

[0039] The quotes from FiG. 1 suggest that a subset of depressed patients view and experience chronic psychological pain as one of the dominant symptoms of severe mood disorder. This subjective experience of depressed patients appears to be as much a component of depression as feelings of hopelessness, worthlessness, decreases in appetite and libido, sleep disorders and thoughts of death and dying. Its intensity may vary over time and may influence the course of the illness (Beriim et al., 2003; Orbach, 2003). New strategies to further investigate chronic psychological pain symptoms are disclosed beiow.

[0040] FlG. 2 illustrates hypothesized interactions between chronic psychological pain 200, physical pain 210, depression 220 and suicide 230. Evidence is presented beiow relevant to the interaction of chronic physical pain and psychological pain; a possible role of chronic physical pain in the development of depression, the contribution of chronic psychological pain 200 in depression; chronic psychological pain 200 as a core component of the depressive process; and that an increase in suicidal behaviors can be associated with chronic psychological pain 200, depression and or chronic physical pain. [0041] FIG. 1 provides examples ^" of five patients who portray chronic intolerable psychological pain prior to committing suicide. Shneidman (Shneidman, 1993; 1998), after reviewing a large number of suicide notes, concluded that without psychological pain there is no suicide. The characteristic unbearable psychological pain associated with depression is a common theme among suicidal patients (Orbach, Mikulincer, Giiboa-Schechtman, & Sirota,

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2003a; Shneidman, 1993). Social factors such as recent losses (personal, occupational, financial) that increase psychological pain also increase the risk for suicide (Arciniegas & Anderson, 2002; Creed, Craig, & Farmer, 1988). Variables such as depression and hopelessness were reported to be inadequate in predicting suicidal behaviors according to a study of sixty outpatients. Rather it was suggested that a general psychological and emotional pain that reaches intolerable intensity is predictive of suicide (Berlim et at., 2003). [0042] It is well-documented that chronic physical pain increases the vulnerability for depression and suicide in susceptible individuals (Bair et a!., 2003; Fishbain, 1999). Estimates of the prevalence of suicidality from a study of 153 non-malignant pain patients referred to a tertiary pain clinic were as follows; 19% of patients had passive suicidal ideation, 13% had active suicidal thoughts, 5% had a current suicide plan and 5% reported a previous suicide attempt. Factors that increase suicidal ideation included a family history of suicide attempts or completions and abdominal pain. Additionally, severe and frequent insomnia and high physical pain intensity increase suicidal ideation, independent of the severity of depression (Smith, Edwards, Robinson, & Dworkin, 2004). [0043] Sn the United States, 90% of the completed suicides are associated with a mental disorder. The lifetime risk for suicides in the genera! U.S. population is approximately 4%. Major depressive disorder has a 20 fold higher rate of suicide, bipolar disorder (BPD) a 15 fold higher rate of suicide than the general population (Institute of Medicine, 2002). Depression and chronic physical pain particularly in the elderly are risk factors for suicide. The systematic evaluation of unbearable psychological pain provides an important additional variable which may be particularly relevant to the assessment of suicidality. [0044] The association between chronic physical pain and increased vulnerability to depression is documented in thousands of patients studied in large clinical populations (Fishbain, 2002; Fishbain et al., 1997; Korszun, 2002; Schatzberg, 2004; Williams et al., 2003; Yap et al., 2003). Chronic pain patients, especially those with multiple symptoms, are at substantially higher risk for depression than patients without pain. Headaches, backaches, abdominal pain,

chest pain and facial pain are the most common pain symptoms associated with depression (Creed et al., 1988; Currie & Wang, 2004; Dohrenwend, Raphael, Marbach, & Gallagher, 1999; Lepine & Briley, 2004; Ohayon & Schatzberg, 2003; Schatzberg, 2004; Smith et al _M 2004). In terms of prevalence, Bair (Bair et al., 2003) concluded from a survey of more than 42 studies including 15,000 patients in seven different clinical settings (e.g., inpatient pain programs, psychiatric, rheumatology, orthopedic, dental, gynecology and primary care clinics) that 48% of the patients treated in pain clinics were depressed. A study by Schatzberg (Schatzberg, 2004) involved 18,980 subjects from several European countries who were randomly selected and interviewed by telephone. Results showed a 4% prevalence rate for major depressive disorder. Of these, 43.4% had at least one chronic (greater than 6 months) physical pain condition which was 4 times the rate reported in patients without depression. Moreover, they found that patients experiencing continuous pain, even for 24 hours, are at higher risk for depression (Schatzberg, 2004). This data is supported by earlier work of Fishbain (Fishbain, 2002) who found that 33/37 studies identified a direct statistical relationship between the severity or frequency of pain and the severity of depression. This same group also reported that depression is more likely to be a consequence of physical pain (15 studies) (Fishbain, 2002; Fishbain et ai., 1997). It could be argued that chronic physical pain predisposes some patients to depression by acting as an inescapable stressor (Blackburn-Munro & Biackburn- Wlunro, 2001). However as noted by Schatzberg (Schatzberg, 2004) a large number of patients develop depression prior to physical pain conditions. [0045] Individuals facing excruciating life stressors such as the suffering associated with the sudden loss of a child, spouse or significant other may experience "unbearable" psychological pain placing them at higher risk for depression and/or suicide. It was reported that 75% of 270 depressed patients experienced a stressful life event in the twelve months prior to depression (Mitchell, Parker, Gladstone, Wilheim, & Austin, 2003). Severe life events are documented to precipitate initial episodes of depression and to increase the vulnerability to future episodes (Mitchell et al., 2003; Paykel, 2003). .

[0046] Is there overlap in regional brain activity between physical pain and cognitive-stimulated psychological pain? The data in FiG. 3A ₁ FiG. 3B, and FiG. 3C, (relating to brain imaging data of regional activationai changes associated with psychological pain paradigms), and FiG. 4A and FiG. 4B (relating to brain imaging data of regional activationai changes associated with anticipation to simulated physical pain) suggest that physical and psychological pain engaged the prefrontal cortex (PFC), anterior cinguiate (AnCg) and insula. Activation of the primary and secondary somatosensory cortices, however, is more commonly associated with responses to simulated and actual physical pain rather than to psychological pain, (in FiG. 3A, FiG. 3B, and FlG. 3C, the subjects were healthy and non-medicated; DLPFC=dorsolateral prefrontal cortex; AnCg=anterior cinguiate; F=femaie, fvfcmaie, yrs=years, R=Right, L=Left, {v1i=middle, and B=Bilaterai.) (In F!G. 4A and FiG. 4B ₁ subjects were healthy and non-medicated; DLPFC=dorsoiateral prefrontal cortex, AnCg=anterior cinguiate; Dorsomedial- dorsomedial PFC; L=left, R=Right, B=Bi!ateral, r=rostrai anterior AnCg ₁ av=anteroventrai AnCg, pos=posterior, and ant=anterior. **in paradigms using cues for painful vs non-painful stimuli, the brain imaging data is for the cued conditions for physical pain. )

[0047] The physical pain pathways are well-described and provide the neural basis for comparisons between subtypes of pain. A meta-analysis of 26 neuroimaging studies reported by Peyron (Peyron, Laurent, & Garcia-Larrea, 2000) was used to identify regional changes in brain activation associated with acute physical pain in healthy subjects and in chronic pain patients. The number of studies reporting increased, decreased or no change in brain activation under the two physical pain conditions are summarized in FIG. 4A and FiG. 4B. Paradigms to study simulated physical pain include exposure to noxious stimuli such as heat, cold water baths, subcutaneous injections (e.g., capsaicin, histamine, ethanoi), electrical muscular pain, and iaser pulses to the skin. Healthy subjects receiving acute physically noxious pain stimuli show activation of the PFC, AnCg ₁ insula, thalamus, cerebellum, parietal and somatosensory cortices but not the amygdala. Acute studies in chronic pain patients show less

consistent activation in response to physical pain stimuli particularly in the PFC and AnCg. Areas of activation in chronic pain patients include the secondary somatosensory cortex, thalamus, cerebellum and parietal regions. Not activated is the primary somatosensory cortex (in contrast to healthy subjects). Neither healthy subjects nor chronic pain patients showed activation of the amygdala in response to acute physical pain.

[0048] Anticipation of pain refers to the expectation by a subject that a noxious physical stimulus wili occur. In these paradigms, a warning signal usually precedes the stimulus and cues the subject of a 'real ⁵ pain stimulus or of a neutral (non-painful) stimulus. The time-frame for the appearance of the stimuli may be known or uncertain. Findings show that fMRi signals increase in the somatosensory cortex in anticipation trials where the timing of the stimulus is known and that the signal is weaker in the uncertain conditions (Porro, Lui, Facchin, Maieron, & Baraldi, 2004). Anticipation activates components of the nociceptive pathway including PFC, insula, AnCg ₁ somatosensory cortices as well as tie thalamus, cerebellum, amygdala and parietal regions. Conversely, anticipation of analgesia (not shown in the Figures) is associated with a decrease in fMRi signals in these same pain-related regions (Wager et al., 2004). [0049] Empathy is characterized in these studies by an ability to 'feel' another's physical pain (Singer et ai., 2004). In empathy studies, subjects are asked to either watch videos of, or observe in real life, experiments where they witness an individual receiving a painful stimulus. Singer et al (Singer et ai., 2004) studied 16 romanticaiiy-involved couples. The experiment involved a > warning signal indicating which one of the partners would receive a 1 -second electric shock. The non-shocked individual, although not seeing the face of the partner, could visualize from an indicator, whether the shock would be mild or stinging. Their results showed that empathy-related responses activate components of the physical pain pathway that includes PFC, AnCg ₁ insula, thalamus, cerebellum and brainstem but with the exclusion of the somatosensory cortices. Similar observations were reported in an fMRi study in which subjects watched video clips of facial expressions of people in pain. Activation was seen

in the PFC, AnCg, insula, thalamus, cerebellum, amygdala and parietal regions but not in the somatosensory cortices (Botvinick et aL, 2005). A third study of empathy asked subjects to rate the degree of pain in subjects viewed from online still photographs of painful situations involving hands and feet (e.g., a picture of someone slamming a foot or hand in a door). Viewing the videos activated the AnCg, insula, thalamus, and cerebellum but not the PFC, somatosensory cortices, amygdala or parietal cortices (Jackson, Meltzoff, & Decety, 2005). Singer (Singer et al., 2004) reports overlapping activation in AnCg and anterior insula to either acute pain to self, anticipation of acute pain to self, or empathy for acute pain to others. However, only a portion of the pain matrix is recruited in response to empathy with the relative absence of somatosensory cortices. [0050] Hypnosis or suggestive techniques such as imagination techniques, used to induce 'physical pain', are shown to increase activation of physical pain-related structures such as the PFC, AnCg, insula, thalamus and primary and secondary somatosensory cortices. Regions not activated include the cerebellum and amygdala (Craig, Reiman, Evans, & Bushneli, 1996; Derbyshire, Whalley, Stenger, & Oakley, 2004; Hofbauer, Rainville, Duncan, & Bushnell, 2001; Raij, Numminen, Narvanen, Hiltunen, & Hari, 2005), which is in contrast to the effects of the anticipation and empathy of physical pain paradigms. These interpretations of the results are limited by the relatively few studies in this area.

[0051] Some of the most consistent data in terms of activation of paiπ- reiated structures comes from induced sadness paradigms. Cognitive stimuli used in paradigms to induce 'sadness' include sad facial expressions, recollection of memories, stories, videos, or a combination of these [(e.g., recalled sad memories and sad facial expressions(George et al., 1995). in contrast to other pain paradigms, induced sadness is associated with consistent reports of amygdala activation. Increasing intensity of sadness is reported to further increase amygdala activity(Blair, Morris, ¹ Frith, Perrett, & Dolan, 1999). Additional areas of activation associated with induced sadness in healthy subjects include the PFC, AnCg, insula, thalamus, cerebellum and parietal cortex

but not the somatosensory cortices.

[0052] To date, only one study investigated social exclusion using neuroimaging. Eisenberger (Eisenberger & Lieberman, 2004; Eisenberger, Lieberman, & Williams, 2003) demonstrated that many of the human brain areas that "light up" during physical pain are also activated during emotional "pain" induced by social exclusion. A relationship was reported between the intensity of the experimentally-induced social defeat and an increase in AnCg activation. The authors suggest that selection pressure on the mammalian brain has resulted in a common pathway shared by physical and psychological pain that may help to promote social bond formation between infants and mothers. [00S3] Of the experimental psychological pain conditions, grief may be one of the most 'severe'. Gundel (Gundel, O'Connor, Uttreli, Fort, & Lane, 2003) used fMRi to measure regional brain changes in 8 females who had experienced the death of a first-degree relative within the past year (mother, father, husband) (depressed subjects were excluded). Pictures and verbal descriptions of the deceased were presented to the subjects. Visual representation with pictures activated the brain regions associated with empathy and induced sadness (AnCg, insula, and PFC). A second fMRl study assessed women who had ended a romantic relationship in the preceding 4 months and were in the grieving process. The subjects were asked to recall sad events about the relationship. Activation and overlap of pain-related structures including the PFC, AnCg, and insula were reported (Najib, Lorberbaum, Kose, Bohning, & George, 2004). Meither study reported activation of the somatosensory cortices. [0054] There is a large literature involving neuroimaging studies of mood disorders. To briefly summarize, primary structures in the pain pathway associated with abnormalities in depression include the PFC, AnCg, insula, amygdala although the direction of change is inconsistent (depression data is not included in the Figures). Nonetheless, a recent review provides evidence for consensus that depressed patients have decreased activation in the subgenual PFC ₅ accompanied by increases in pre-genual AnCg activity, increases in anterior insula and ventrolateral prefrontal cortex as well as increases in

amygdala activity (Smith & Cavanagh, 2005). Increases in amygdala activation are also reported in sadness induced paradigms in MDD patients (Surguladze et at., 2005).

[0055] Evidence from this review supports the importance of psychological pain and the development of the "Mee-Bunney Scale", a validated reliable instrument for the quantification of the intensity of psychological pain. The MBS may be utilized to assess the incidence of psychological pain in a population of bipolar, major depressive disorder and possibly, schizophrenic patients. The MBS may also be utilized to study the predicted relationship between psychological pain and suicidal behavior. The MBS may further be utilized for the identification of effective medications to decrease psychological pain. The MBS may also be utilized to further investigate a putative psychological pain system through neuroimaging technology, to investigate efficacy of psychotherapeutic interventions to decrease psychological pain, and to utilize psychological pain as a phenotype for genetic studies of depression. [0056] The MBS can be administered in the ER or health care professional's office to assess the level of psychological pain. The use of the MBS may provide evidence-based information for the (a) inclusion of the evaluation of psychological pain as a potential core system in the DSM criteria for the diagnoses and characterization of BPD, MDD and SZ and (b) utilization of unbearable psychological pain as a potential important predictor of imminent suicidal behavior.

[0057] Currently, there are no population studies that have assessed the incidence of psychological pain in bipolar disorder, major depressive disorder or schizophrenia. Despite the fact that a number of scales include items relevant to psychological pain, it has not been independently studied. [0058] The identification of psychological pain may be valuable, in a subset of depressed patients, as a phenotype for genetic studies of depression. Using the extreme of this phenotype to provide for a more homogeneous genetic population may enrich for loci predisposing to a subtype of depression and other major mood disorders.

[0059] The central point of the information presented here is illustrated by the literary figure who stated "the gray drizzle of horrors induced by depression takes on the quality of physical pain". It is suggested that the psychological pain of severe depression may be quantitatively and qualitatively unique in its severity, is usually perceived as worse than any physical pain that the patient had experienced and is a critical component of suicidal behavior. [0060] In summary, a significant body of data derived from functional neuroimaging studies provides convergent evidence concerning brain structures implicated in physical pain, and psychological pain with the AnCg, insula and the prefrontal cortex being involved in all of these conditions while the somatosensory cortices may be uniquely activated in physical pain. On the other hand, little data is available concerning the possible pathophysiological and metabolic substrates of psychological pain and virtually nothing is known about those genes that might mediate psychological pain. [0061] To achieve the objectives and ends described above, and to overcome the limitations of the prior art, the present invention includes a method 600 (FIG. 6) for measuring psychological pain including a step 610 of providing a scale indicative of mental pain being experienced by a person and a step 620 of using the scale to assess the level of mental pain experienced by the person. [0062] In accordance with another aspect of the invention, a method 700

(FIG. 7) for providing characterizations and measurements of psychological pain includes a step 710 of providing a scale indicative of mental pain being experienced by a person and a step 720 of using the scale in the diagnosis, treatment, and therapeutic development of pharmaceutical compounds to treat psychological, and other forms of, pain.

[0063] Jn accordance with yet another aspect of the invention, a method

800 (FIG. 8) of screening a subject includes a step 810 of assessing psychological pain experienced by a subject via the use of a psychological pain scale and a step 820 of providing a classification regarding the subject based upon the psychological pain scale output. [0064] In accordance with another aspect of the invention, a method 900

(FiG. 9) of evaluating psychological pain of a patient includes a step 910 of assessing a level of psychological pain experienced by the patient via the use of a psychological pain scale at different times during each of a plurality of sessions, a step 920 of monitoring the level of psychological pain experienced by the patient during each of the sessions based upon the psychological pain scale and a step 930 of providing a determination regarding the psychological pain of the patient based upon changes observed in the psychological pain scale output. [0065] In accordance with yet another aspect of the invention, a method

1000 (FIG. 10) of evaluating effectiveness of a psychological pain treatment for a patient includes a step 1010 of assessing a level of psychological pain experienced by a patient via the use of a psychological pain scale at different times during each of a plurality of sessions, a step 1020 of monitoring the level of psychological pain experienced by the patient during each of the sessions based upon a psychological pain scale and a step 1030 of providing a determination regarding psychological pain relief based upon the changes observed in the psychological pain scale output.

[0066] The foregoing description of the invention illustrates and describes the present invention. Additionally, the disclosure shows and describes only the preferred embodiments of the invention, but it is to be understood that the invention is capable of use in various other combinations, modifications, and situations and is capable of changes or modifications within the scope of the inventive concept as expressed herein, commensurate with the above teachings, and/or the skill or knowledge in the art of psychological pain measurement. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended that the appended claims be construed to include alternative embodiments.