An innate brainstem self-other system involving orienting, affective responding, and polyvalent relational seeking: Some clinical implications for a "Deep Brain Reorienting" trauma psychotherapy approach.

Underlying any complex relational intersubjectivity there is an inherent urge to connect, to have proximity, to engage in an experience of interpersonal contact. The hypothesis set out here is that this most basic urge to connect is dependent on circuits based in three main components: the midbrain superior colliculi (SC), the midbrain periaqueductal gray (PAG), and the mesolimbic and mesocortical dopamine systems originating in the midbrain ventral tegmental area. Firstly, there is orienting towards or away from interpersonal contact, dependent on approach and/or defensive/withdrawal areas of the SC. Secondly, there is an affective response to the contact, mediated by the PAG. Thirdly, there is an associated, affectively-loaded, seeking drive based in the mesolimbic and mesocortical dopamine systems. The neurochemical milieu of these dopaminergic systems is responsive to environmental factors, creating the possibility of multiple states of functioning with different affective valences, a polyvalent range of subjectively positive and negative experiences. The recognition of subtle tension changes in skeletal muscles when orienting to an affectively significant experience or event has clinical implications for processing of traumatic memories, including those of a relational/interpersonal nature. Sequences established at the brainstem level can underlie patterns of attachment responding that repeat over many years in different contexts. The interaction of the innate system for connection with that for alarm, through circuits based in the locus coeruleus, and that for defence, based in circuits through the PAG, can lay down deep patterns of emotional and energetic responses to relational stimuli. There may be simultaneous sequences for attachment approach and defensive aggression underlying relational styles that are so deep as to be seen as personality characteristics, for example, of borderline type. A clinical approach derived from these hypotheses, Deep Brain Reorienting, is briefly outlined as it provides a way to address the somatic residues of adverse interpersonal interactions underlying relational patterns and also the residual shock and horror of traumatic experiences. We suggest that the innate alarm system involving the SC and the locus coeruleus can generate a pre-affective shock while an affective shock can arise from excessive stimulation of the PAG. Clinically significant residues can be accessed through careful, mindful, attention to orienting-tension-affect-seeking sequences when the therapist and the client collaborate on eliciting and describing them.

Brainspotting: sustained attention, spinothalamic tracts, thalamocortical processing, and the healing of adaptive orientation truncated by traumatic experience.

We set out hypotheses which are based in the technique of Brainspotting (Grand, 2013) [1] but have wider applicability within the range of psychotherapies for post-traumatic and other disorders. We have previously (Corrigan and Grand, 2013) [2] suggested mechanisms by which a Brainspot may be established during traumatic experience and later identified in therapy. Here we seek to formulate mechanisms for the healing processing which occurs during mindful attention to the Brainspot; and we generate hypotheses about what is happening during the time taken for the organic healing process to flow to completion during the therapy session and beyond it. Full orientation to the aversive memory of a traumatic experience fails to occur when a high level of physiological arousal that is threatening to become overwhelming promotes a neurochemical de-escalation of the activation: there is then no resolution. In Brainspotting, and other trauma psychotherapies, healing can occur when full orientation to the memory is made possible by the superior colliculi-pulvinar, superior colliculi-mediodorsal nucleus, and superior colliculi-intralaminar nuclei pathways being bound together electrophysiologically for coherent thalamocortical processing. The brain's response to the memory is "reset" so that the emotional response experienced in the body, and conveyed through the paleospinothalamic tract to the midbrain and thalamus and on to the basal ganglia and cortex, is no longer disturbing. Completion of the orientation "reset" ensures that the memory is reconsolidated without distress and recollection of the event subsequently is no longer dysphorically activating at a physiological level.

Autonomic dysregulation and the Window of Tolerance model of the effects of complex emotional trauma.

This paper reviews the Window of Tolerance model of the long-term effects of the severe emotional trauma associated with childhood abuse, a model which can also be applied to adult trauma of sufficient severity to cause post-traumatic stress disorder, chronic dysthymic disorders and chronic anxiety disorders. Dysfunctional behaviours such as deliberate self-harm and substance abuse are seen as efforts to regulate an autonomic nervous system which is readily triggered into extreme states by reminders of the original traumatic events. While midbrain areas such as the periaqueductal gray mediate instant defence responses to traumatic events and their memory triggers it is proposed that ascending monoaminergic tracts are implicated in longer-term changes in mood and arousal. An imbalance of ascending dopaminergic tracts may drive rapid fluctuations in level of arousal and in the associated mood, drive and motivation. Animal models of depression frequently use traumatic experiences of pain, isolation or social defeat to induce changes in mesolimbic and mesocortical dopamine systems which may alter prefrontal cortical control of midbrain defence responses. A focus on the pharmacology of the Window of Tolerance could provide advances in drug treatments for promoting emotional regulation in those who are suffering from the chronic sequelae of traumatic experiences.

Psychotherapy as assisted homeostasis: activation of emotional processing mediated by the anterior cingulate cortex.

Although psychotherapy is successful in altering emotional distress, the biological mechanism by which it achieves this has not been the subject of intensive neurobiological investigation. Mindful processing of emotion has been proposed [Mindfulness-Based Cognitive Therapy for Depression, The Guilford Press, New York, 2002] to be a key factor in prevention of relapse in depressive illness and here that hypothesis is developed and extended to include other conditions in which emotion processing may be obstructed or dysregulated. Cognitive therapy, interpersonal psychotherapy, psycho-dynamic psychotherapy and dialectical behaviour therapy, each in a different way and with a distinct emphasis, encourage awareness of emotions and their associated cognitions and biographies, and their varying success may depend on the degree to which they achieve activation of internal healing processes. In eye movement desensitisation and reprocessing (EMDR), the selected target is formatted for endogenous processing which is facilitated and accelerated by eye movements or alternating bilateral auditory or tactile stimulation. The ability to sustain focussed attention on the affect and its visceral, cognitive and biographical components is postulated to activate a homeostatic process of distress resolution, seen most clearly in treatment of post-traumatic stress disorder (PTSD) with EMDR, in which resolution of distress can be intense and rapid while therapist input is non-directive, although supportive, empathic, and non-judgemental. Once the therapist has helped to frame the questions, the patient's brain will find the answers needed for the resolution of the distress and all the components of the traumatic event, whether visceral, cognitive, affective or interpersonal. The anterior cingulate cortex, especially the dorsal and rostral components, is suggested to be the key neurobiological substrate for the efficacious psychotherapeutic relief of distress, and relevant functional neuroimaging studies are summarised. One limitation of some previous imaging studies of emotion is that they have tended to use mild stimuli to discrete emotions. An alternative approach would be to image the brain during reprocessing of an unpleasant event which has profoundly affected the person so that the associated intense emotions could be clearly labelled and correlated with changes in regional brain functioning.

The role of dysregulated amygdalic emotion in borderline personality disorder.

Borderline personality disorder (BPD), is a condition that has a high mortality and is associated with much distress for the sufferers as well as with difficult management problems for health professionals. Taking emotional dysregulation as the core feature of BPD, the authors propose that the disorder arises from impaired modulation of subcortical inputs to consciousness. We hypothesize that the amygdaloid complex, and its connections with thalamus, cingulate cortex and insular cortex are critical in the development and maintenance of the disorder. If this is the case, peptides such as galanin, somatostatin and cholecystokinin will be the most important neurotransmitters, thus explaining the relative lack of efficacy of standard antipsychotic and antidepressant drugs.

Organochlorine insecticides in substantia nigra in Parkinson's disease.

The concentrations of organochlorine (OC) compounds in the substantia nigra (SN) were compared in Parkinson's disease (PD) with concentrations in brain from cortical Lewy body dementia (CLBD), Alzheimer's disease (AD), and nondemented nonparkinsonian controls (CON). The levels of the gamma isomer of hexachlorocyclohexane (gammaHCH, lindane) were significantly higher in PD tissues (mean +/- SD: 0.56 +/- 0.434 microg/g lipid) than in the other three groups (CLBD 0.052 +/- 0.101 microg/g lipid; AD none detected; CON 0.125 +/- 0.195; all differences from PD significant at p < .05, Mann-Whitney U-test). Dieldrin (HEOD) was higher in PD brain than in AD or control brain, while 1,1'-(2,2-dichloroethenyl diene)-bis(4-chlorobenzene) (p,p-DDE) and total Aroclor-matched polychlorinated biphenyls (matched PCBs) were only higher in PD substantia nigra when these concentrations were compared with those of CLBD. These findings are not inconsistent with the hypothesis derived from epidemiological work and animal studies that organochlorine insecticides produce a direct toxic action on the dopaminergic tracts of the substantia nigra and may contribute to the development of PD in those rendered susceptible by virtue of cytochrome P-450 polymorphism, excessive exposure, or other factors.

Abnormal content of n-6 and n-3 long-chain unsaturated fatty acids in the phosphoglycerides and cholesterol esters of parahippocampal cortex from Alzheimer's disease patients and its relationship to acetyl CoA content.

The long-chain fatty acid composition of cholesterol esters, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) from parahippocampal cortex of Alzheimer's disease (AD) patients and control subjects was examined. In general the PC fraction contained less polyunsaturated long-chain fatty acids than did PE, PS or PI. Of the n-6 polyunsaturated long-chain fatty acids, PI contained the greatest incorporation of these acids followed by PE. There were significant differences between controls and AD patients in total n-6 EFAs. Arachidonic acid (C20:4n-6) was the predominant fatty acid of this family found to be present. In AD, PE and PS showed a deficit of adrenic acid (C22:4n-6) content and PE also contained less arachidonic acid. In AD subjects, the cholesterol esters contained significantly less n-3 polyunsaturated fatty acids with, specifically, a reduction in alpha-linolenic acid. Acetyl CoA content of hippocampal cortex was greater in AD patients than in control subjects indicating either an increased extent of oxidative metabolism or a failure to utilise acetyl CoA for anabolic processes. Abnormal magnitude of oxidative processes could give rise to the biosynthesis of PE and PS species containing less n-6 polyunsaturated fatty acids than occurs in control subjects.

Diorthosubstituted polychlorinated biphenyls in caudate nucleus in Parkinson's disease.

As it had previously been demonstrated that there were reduced brain dopamine concentrations in monkeys who had been given polychlorinated biphenyls (PCBs) chronically, we hypothesized that organochlorine compounds in general, and PCBs in particular, might be important in the pathogenesis of Parkinson's disease (PD). In a study of caudate nucleus obtained post mortem from patients with Parkinson's disease and from controls, there were significantly higher concentrations of the organochlorine insecticide dieldrin and the PCB congener 153 in the PD tissue. DDE, PCB congener 180, and total PCBs (matched with a commercial preparation) also tended to be higher in Parkinson's disease tissue. We think that this is important preliminary evidence that diorthosubstituted PCBs may contribute to the pathogenesis of Parkinson's disease, and a greater presence of organochlorine insecticides in the PD tissue suggests that this may be in part the explanation for the association between PD and rural living.

High density lipoprotein fatty acids in dementia.

High density lipoproteins (HDL) are small plasma particles which may be able to pass through the blood-brain barrier. We have therefore studied the fatty acids of HDL in patients with dementia to determine whether the changes are consistent with those previously reported in brain tissue. The HDL phospholipid and the HDL cholesteryl ester both showed reduced concentrations of arachidonic acid (20:4n6) as compared to normal controls. HDL may be a useful plasma fraction for study of lipids in neurodegenerative diseases.

Depression: immunological resignation of the will to live?

Evolution is assumed to promote the survival of the fittest by the greater success of the reproductive potential of those with the characteristics most suited to their environment. Little thought is given to how those least adapted fail to survive to reproduce. If the species, rather than the individual, has a drive to adaptation and survival, there should be a specific mechanism for those least adapted to withdraw from life. The immunological changes accompanying depression may facilitate heart disease, infection, parasitic infestation or other ill health, so that depression is a mechanism for those least resilient, or faced with most adversity, to succumb to illness. If depression is a state facilitating withdrawal from competition for reproductive success, major depressive illness may be the inappropriate and spontaneous occurrence of a mental state which has advantages for the species in allowing those 'least fit' to fail to survive. This hypothesis gives an empirically testable challenge to the view that the species has no evolutionary drive to survival and increased adaptedness to the environment, as well as explaining the more and more frequent occurrence of a specific mental state and its associated changes in the immune system.

Parapsychotic grief, theory of mind and the concept of the soul.

The ability to deceive is regarded as the best evidence of the cognitive ability separating humans from other primates. An alternative would be to look at the concept of the soul, which has an archetypal significance, emerging in various geographically remote cultures over the course of history. The soul will be an elusive but not an impossible concept to study with neuroimaging. In parapsychotic grief the decreased may appear to the bereaved person without these hallucinations being considered as indicative of mental illness. If this is the sort of normal human experience which has led to the emergence of the belief in the immortality of the soul it may be a useful starting point for defining the neuroanatomical basis of souls which do not necessarily seek to deceive. As the human prefrontal cortex expanded and developed and strove to understand mental activity derived from subcortical structures the human attained an awareness of his own mind which has been construed as a separable insubstantial but indestructible entity. This idea would be bizarre if it were not archetypal and therefore must be closely linked to the development of the human central nervous system.

Organotin compounds in trimethyltin-treated rats and in human brain in Alzheimer's disease.

As blood tin concentrations are elevated in Alzheimer's disease and as some low molecular weight organotin compounds are neurotoxic, we have attempted to detect organotins in brain in Alzheimer's Disease. First we measured the concentration of trimethyltin (TMT) in the brains of rats which had been exposed to memory-impairing concentrations of TMT and, as the method of linking hydride generation, cryogenic trapping, gas chromotographic separation and atomic absorption spectrophotometric detection permitted the measurements of organotin compounds when the total tin was greater than 0.2 nanograms, we applied these techniques to human brain tissue, some of which showed neuropathological evidence of Alzheimer's Disease. No low molecular weight organotin compounds were detected in the human brain tissue, but it is possible that tin may be complexed with large organic molecules, the hydrides of which would not be volatile, but which could be identified by liquid chromatography.

Organochlorine compounds in human brain.

Having observed polychlorinated biphenyls (PCBs) in brain tissue obtained post mortem from two men we have carried out a study of organochlorine compounds in frontal cortex from patients with Parkinson's disease (PD) and from controls. No PCBs were found in any of those samples. There was no difference in the concentration of the DDT metabolite pp'-DDE in the PD brain samples. Dieldrin (HEOD) was significantly decreased in PD brain when analysed by lipid weight. While these findings would not support the hypothesis that PCBs may contribute to the development of Parkinson's disease in humans it remains possible that they may cause damage to the basal ganglia before being displaced from brain tissue.

Enhanced GABAb receptor-mediated transmission in alcohol-dependence syndrome.

We have studied the GABAb receptor-mediated neurotransmissions of alcoholic patients by administering baclofen 10 mg orally and measuring the growth hormone (GH) response. There was a minimal GH response to the baclofen in one of eight control subjects and a greater GH response in 11 of the 16 alcoholic patients. There is thus evidence for increased transmission at the GABAb receptor in detoxified patients with alcohol-dependence syndrome.

Neurasthenic fatigue, chemical sensitivity and GABAa receptor toxins.

Following observation of fatigue syndromes in people who have been occupationally exposed to pesticides and insecticides which exert their toxicity through the GABAa receptor, we have formulated the hypothesis that fatigue syndromes in general may be secondary to altered sensitivity of the GABAa receptor. We discuss the possible involvement of organochlorine compounds which are widespread in the environment. Organophosphate compounds may have similar toxic effects through damaged cholinergic input to the dentate gyrus of the hippocampus where cholinergic and GABAergic transmission are closely linked.