Amnesias and dementias
Patients with lesions to the hippocampocentric division of the limbic system manifest severe memory deficits (Markowitsch 2000). Some differences in the clinical presentation may be related to the exact location and extension of the damage, and its nature. The common manifestations are those of a global amnesia where the patient is
unable to encode, associate, and retrieve new information (anterograde amnesia). In addition there is also some degree of amnesia for events before the brain damage but temporally close to it (retrograde amnesia). The remote memory is well preserved. The patient H.M., who underwent bilateral resection of the medial temporal lobe for pharmacologically intractable epilepsy, is a classical example of a pure global amnesic (Figure 11.6) (Scoville and Milner, 1957). Despite the severity of the short-term memory problems his long-term memory and insight were relatively preserved.
Loss of insight can be associated with confabulation (the spontaneous narrative report of events that never happened) in patients with diencephalic amnesias due to lesions of the mammillary bodies, the thalamic nuclei and their interconnections. Confabulation can be severe in chronic alcoholics with Korsakoff’s syndrome, especially if the pathology affects the normal activity of the medial orbitofrontal and anterior cingnulate cortex. ln a 32-year-old alcoholic patient that confabulated for 6 weeks, measurement of cerebral perfusion using single photon emission computed tomography, showed hypoperfusion of the anterior and mediodorsal thalamic nuclei, anterior cingulate and orbitofrontal cortex (Benson et al., 1996). A second single photon emission computed tomography repeated after the confabulation stopped showed a ‘normalization’ of the orbitofrontal and anterior cingulate perfusion. The anterior and mediodorsal thalamic nuclei remained hypoperfused and the patient continued to suffer with profound amnesia (for a review of the anatomy of confabulation see Schneider, 2008).
ln patients with vascular thalamic lesions (such as case A.B. reported by Markowitsch et al., 1993) the extension of the damage to the mammillo-thalamic tract is the best predictor of the severity of the memory deficit (Von Cramon et al., 1985).
In patients with colloid cysts of the third ventricle, the surgical removal of the benign tumour can damage the fornix and result in anterograde amnesia, although it is seemingly not as severe as that seen in diencephalic patients (Aggleton, 2008). Another form of hippocampocentric memory dysfunction is associated with lesions to the posterior parahippocampal cortex, retrosplenial cingulate cortex, and posterior precuneus (Valenstein et al., 1987). These patients, in addition to memory deficits, show difficulties in spatial orientation due to the inability to derive directional information from landmark cues in familiar and new environments (Vann et al., 2009). Reduced metabolism of the retrosplenial cortex has also been reported in patients with mild cognitive impairment (Nestor et al., 2003) and early Alzheimer’s disease (Minoshima et al., 1997).
More recently, a combined cortical morphometry and diffusion imaging study found reduced cortical thickness and white matter abnormalities of these regions (Acosta-Cabronero et al., 2010). Compared to surrounding areas, the parahippocampal, posterior cingulate, and precuneus regions also have a faster rate of atrophy in pre-symptomatic Alzheimer’s disease patients (autosomal dominant mutation carriers) (Scahill et al., 2002). Reduced fractional anisotropy has also been found in the cingulum, hippocampus and the posterior corpus callosum of cognitively intact subjects with increased genetic risk of dementia (APOE 4 carriers) (Persson et al., 2006). Preliminary evidence suggests that diffusion changes in neurodegenerative disorders are likely to reflect severity of underlying white matter pathology. Xie et al. (2005) reported a significant positive correlation between reduced fractional anisotropy values, atrophy of the hippocampus and decline in the mini-mental state examination scores in patients with Alzheimer’s disease. ln a transgenic mouse model over-expressing beta-amyloid precursor protein, the diffusivity parameters were significantly correlated with the severity of Alzheimer’s disease-like pathology in the white matter (Song et al. 2004). In humans, Englund et al. (2004) conducted a parallel post-mortem neuropathological examination and fractional anisotropy quantification of two brains with dementia and reported that the degree of white matter pathology correlated significantly with gradually lower fractional anisotropy values sampled in fifteen regions of interest. Overall, these studies suggest that reduced fractional anisotropy in Alzheimer’s disease may reflect white matter axonal degeneration and myelin loss following neuronal degeneration of cortical neurons.
The clinical profile of neurodegenerative disorders varies according to the network affected by the illness. In advanced Alzheimer’s disease, for example, the extension of the disease to the olfactory (orbitofrontal-amygdala) division is associated with clinical manifestations such as semantic deficits, language difficulties, personality changes and other behavioural symptoms (e.g. aggression, dishinibition, etc.), which are not present if the pathology is limited_to the hippocampocentric division. In the temporal variant of the fronto-temporal dementia and in semantic dementia the white matter abnormalities (Borroni et al., 2007; Agosta et al., 2010) involve the olfactory division first, while damage to the hippocampocentric division occurs later as the disease progresses, involving other cognitive domains such as memory and spatial orientation.
Temporal lobe epilepsy
In patients with unilateral temporal lobe epilepsy the damage to the limbic white matter tracts, such as the fornix (Concha et al., 2005) and the uncinate fasciculus (Diehl et al., 2008), is diffuse and often extends contralaterally from the side of the suspected seizure. In temporal lobe epilepsy patients with mesial hippocampal sclerosis, the decreased fractional anisotropy of the fornix fibres is due to reduced axonal diameter and myelin content (Concha et al., 2010). The diffusion changes in the left uncinate fasciculus correlate with the severity of the deficits in delayed recall (Diehl et al., 2008). Preliminary data also suggest, that in patients with temporal lobe epilepsy undergoing surgery, the pre-operative tractography assessment of the lateralization pattern of the temporal tracts can help to predict naming deficits after the operation (more left lateralized patients showed worse postoperative deficits) (Powell et al., 2008).
In some patients with temporal lobe epilepsy the behavioural symptoms resemble those commonly observed in the Kluver-Bucy syndrome. In the 1930s, Kluver and Bucy conducted a series of experiments in rhesus monkeys that consisted of bilateral surgical removal of the anterior temporal lobe, which include the amygdala and temporal pole (Kluver and Bucy, 1939). After the operation the animals showed a strong tendency to examine objects orally (hyper-orality), an irresistible impulse to touch (hypermetamorphosis), loss of normal anger and fear responses, increased sexual activity, and inability to recognize visually presented objects. The first Kluver-Bucy syndrome in humans was described in a patient who received bilateral temporal resection (Terzian and Ore, 1955), but it is usually a condition that clinicians obsen/e in patients with herpes or paraneoplastic encephalitis, tumours, or traumatic brain injury involving the anterior temporal and orbitofrontal cortex (Hayman et al., 1998; Zappala‘ et al., 2012).
ln children with temporal lobe epilepsy, single-photon emission computed tomography reveals hypoperfusion of the basal ganglia and the adjacent frontal and temporal limbic regions. Most of the patients recover after the acute phase, but those with abnormal diffusivity of the temporal and frontal white matter tracts exhibit long-term mental retardation, epilepsy, and persistent oral tendency (Maruyama et al., 2009). Some temporal lobe epilepsy patients present with Geschwind’s syndrome, a characteristic
change in personality consisting of unusual tendencies to write extensively and in a meticulous manner (hypergraphia), excessive and circumstantial verbal output, deepened cognitive and emotional responses (e.g. excessive moral concerns), viscosity of thought, altered sexuality (usually lack of interest), and hyper-religiosity (Waxman and Geschwind, 1974). The emergence of psychotic symptoms in temporal lobe epilepsy is associated with white matter changes extending to the frontal pathways (Fliligel et al.,2006). Behavioural symptoms can respond to surgery. Mitchell et al. (1954) described a case of temporal lobe epilepsy with fetish behaviour. The patientreported highly pleasurable ‘thought satisfaction’ derived from looking at a safety-pin and sought seclusion in a lavatory to indulge it. Unfortunately the fetish object also triggered severe seizures, which required surgical treatment. Relief not only of the epilepsy but also of the fetishism followed the temporal lobectomy.
Psychopathic personality disorder (psychopathy) is characterized by features of emotional detachment and antisocial traits (Patrick et al., 1993), and is strongly associated with criminal behaviour and recidivism (Hare et al., 1999). Since the report of the case of Phineas Gage (Figure 11.7) (Harlow, 1848), who displayed ‘acquired sociopathy‘ following frontal lobe injury (Damasio et al., 1994), the orbitofrontal cortex and other regions of the prefrontal cortex have been considered important for personality and social behaviour (Damasio, 2000). For example, the orbitofrontal cortex is crucial tosuccessful reversal learning in which previously rewarded stimuli are associated with punishment. Reversal learning is significantly impaired in adult psychopaths (Budhani et al., 2006) and in young people with psychopathic traits (Budhani, 2005). It has also been reported that violent personality disordered offenders have reduced prefrontal cortex grey matter volume (Raine et al., 2000) and glucose metabolism (Raine et al., 1997), and impaired orbitofrontal cortex activation during aversive conditioning (\/eit et al., 2002).
In contrast, other researchers have argued that amygdala dysfunction is central to the affective deficits and impairs moral socialization of psychopathy (Blair, 2007a). This latter view is supported by evidence that psychopaths show performance deficits in tasks sensitive to amygdala damage (Levenston et al., 2000; Blair et al., 2001), and have significantly reduced amygdala volume (Tiihonen et al., 2000) and decreased amygdala activation during verbal learning (Kiehl et al., 2001) and facial fear processing (Deeley et al., 2006). Furthermore, stimulation of the amygdala can manifest with irritability, aggression, violent outbursts, and antisocial behaviour. More recently, the dichotomy between researchers postulating whether orbitofrontal cortex or amygdala dysfunction is central to psychopathy (Abbott, 2001) has narrowed; and it has been suggested instead that the social and emotional deficits of psychopaths may reflect an altered interaction between orbitofrontal cortex and amygdala (van Honk and Schutter, 2006; Blair, 2007b). This view has received support from a recent study that used tractography to measure the volume and integrity of the connections between orbitofrontal cortex and amygdala in psychopaths (Figure 11.7) (Craig et al., 2009). A significantly reduced fractional anisotropy was reported in the uncinate fasciculus of psychopaths compared to healthy subjects with similar age and intelligence. A correlation between measures of antisocial behaviour (as assessed by the Psychopathy Checklist) and anatomical differences in the uncinate fasciculus was also reported. To confirm that these findings were specific to the limbic amygdala-orbitofrontal cortex network, other two ‘non-limbic’ control tracts connecting the posterior visual areas to either amygdala or orbitofrontal cortex were studied, and no significant betvveen-group differences were found. These results suggest that abnormalities in a specific amygdala-orbitofrontal cortex network underpin the neurobiological basis of psychopathy.
The limbic system supports emotion, motivation, and memory functions that are often impaired in schizophrenia. Negative symptoms (e.g. anhedonia) are thought to derive from hypofunctioning of the lirnbic system, while some positive symptoms (e.g. hallucinations) have been attributed to its hyperactivity. In a recent review of neuroimaging studies in patients with auditory hallucinations, the anterior cingulate cortex and the medial temporal regions are among the limbic structures that were consistently reported to be activated during auditory hallucinations (Allen et al., 2008).
Abnormalities of both myelin and oligodendroglial architecture and aberrantly located neurons in myelinated fibre bundles have been found in limbic regions (mainly frontal and anterior temporal) of patients with schizophrenia (Akbarian et al., 1996; Davis et al., 2003). Decrased volume of hippocampus (Bilder et al., 1995) medial temporal lobe, insula, anterior cingulate, and thalamus (Honea et al., 2005) has also been reported. Voxel-based (Kublcki et al., 2002; Kanaan et al., 2009), region-of-interest, and tractography (Jones et al., 2005; 2006) studies in patients with schizophrenia reported micro-structural changes in the cingulum (Fujiwara et al., 2007), uncinate fasciculus (Mclntosh et al., 2008), fornix (Kuroki et al., 2006; Takei et al., 2008), and the anterior thalamic radiations (Mclntosh et al., 2008). However, larger studies (Kanaan et al., 2009) and a recent meta-analysis (Ellison-Wright, 2009) suggest that the reported deficits are likely to be part of a wider process rather than be specific to limbic tracts.
Depression and bipolar disorder
Neuroimaging studies show that the subgenual cingulate region (BA 25) is metabolically overactive in depressed patients and its activation reduces with the antidepressant effect of pharmacological treatment (Mayberg et al., 2000), electroconvulsive therapy (Nobler et al., 2001), and transcranial magnetic stimulation of more dorsal frontal regions (Mottaghy et al., 2002). Mayberg et al. (2005) have also shown that chronic direct deep brain stimulation of the white matter fibres adjacent to the subgenual cortex resulted in a significant remission of depression in four of six patients with treatment-resistant depression (Figure 11.8). The antidepressant effect was associated not only with a reduction in the local metabolism of the subgenual region, but also with increased metabolism of dorsal cingulate and other prefrontal areas connected to the subgenual cortex. A recent preliminary tractography study in adolescents with major depressive disorder reported lower fractional anisotropy in the white matter tract connecting the subgenual cingulate region to the amygdala in the right hemisphere (Cullen et al., 2010).
Post-mortem histological studies in patients with bipolar affective disorder have found a reduction in the number and density of glial cells (Ongiir et al., 1998; Webster et al., 2005) and decreased neuronal density in the subgenual region of the orbitofrontal cortex (Bouras et al., 2001) and in the dorsolateral prefrontal areas (BA 9) (Rajkowska et al., 2001). Myelin abnormalities in bipolar affective disorder may be related to a decreased expression of genes involved in myelin synthesis and regulation (Aston et al., 2005). These histological findings are supported by neuroimaging studies that reported a general increase in white matter hyperintensities on MRI images (Altshuler et al., 1995) and selective reduced white matter density (Bruno et al., 2004), together with decreased cortical metabolism and volume in the subgenual region (Drevets et al., 1997) of adults with a diagnosis of bipolar affective disorder. Findings from diffusion imaging studies using region-of-interest or voxel-based approaches have been inconsistent with reports of both decreased (Adler et al., 2004; Versace et al., 2008) and increased (Haznedar, 2005; Versace et al., 2008) fractional anisotropy in bipolar disorder compared to healthy controls. Tractography of the subgenual-amygdala connections showed increased tract volume (Houenou et al., 2007) and reduced fractional anisotropy in the uncinate and anterior thalamic projections (Mclntosh et al., 2008). In a recent single case study, a patient with a history of bipolar disorder and intractable recurrent depression following a right thalamic stroke underwent deep brain stimulation of the subgenual cortex. The patient died 16 months after the implants were positioned without a significant clinical response. A high resolution diffusion imaging dataset acquired post-mortem revealed markedly reduced Iimbic projections from the thalamus to the subgenual cortex and amygdala in the stroke-affected (right) hemisphere. The authors concluded that reduced Iimbic connections assessed with diffusion imaging could be a contraindication to deep brain stimulation for depression (McNab et al., 2009).
Current anatomical models suggest a network composed of the medial orbitofrontal cortex, the anterior-dorsal cingulate and the striatum underpins obsessive-compulsive disorder. Functional and structural imaging studies support this model (Radua and Mataix-Cols, 2008). A recent study, for example, found increased functional connectivity between the striatum and the orbitofrontal cortex (Harrison et al., 2009). The activity of the regions involved in obsessive-compulsive disorder can be reduced with the surgical severing or the electrophysiological inactivation of their interconnecting fibres. The white matter of the anterior-dorsal cingulate and medial frontal regions are the common targets for the treatment of drug-resistant obsessive-compulsive disorder with deep brain stimulation and psychosurgery (i.e. cingulotomy and capsulotomy). The surgical disconnection causes distant structural changes to the interconnected regions as suggested by a study that showed that individuals undergoing cingulotomy had significant reductions in the volume of the caudate nucleus several months after the operation (Rauch et al., 2000). The anatomical changes in the orbitofrontal cortex are less consistently reported despite clear evidence of its altered activity in obsessive compulsive disorder (Radua and Mataix-Cols, 2008; Harrison et al., 2009). Together, the structural and functional imaging studies suggest that, in obsessive compulsive disorder, the primary anatomical abnormalities occur in the striatum with a distant hodological effect on the paralimbic areas of the anterior cingulate and medial orbito-frontal regions.
Autism spectrum disorder
It has been suggested that some of the social and communication abnormalities typically found in autism spectrum disorder are due to abnormalities in Iimbic structures (Damasio and Maurer, 1978) and perhaps also in their connectivity (Courchesne and Pierce, 2005; Wickelgren, 2005). Early post-mortem investigations of both adults and children with autism reported reduced neuronal size and increased cell packing in the hippocampus, amygdala and, to a lesser degree, the enthorinal cortex, mammillaiy bodies and septal nuclei (Bauman and Kemper, 1985; Raymond et al., 1996; Palmen et al., 2004; Bauman and Kemper, 2005). Recent in vivo voxel-based morphometry studies reported signiﬁcant differences in the anatomy of limbic regions, but with contrasting results with respect to the white matter compartment (Herbert et al., 2003; Barnea-Goraly et al., 2004; Boddaert et al., 2004; Kwon et al., 2004; McAlonan et al., 2005; Salmond et al., 2005; Lee et al., 2007; Lee et al., 2009). For example, several groups reported decreased grey and white matter volumes in the inferior temporal regions and fusiform gyrus in both autism and Asperger’s syndrome in young adults (Boddaert et al., 2004; Kwon et al., 2004; McAlonan et al., 2005; Salmond et al., 2005). Herbert et al. (2004) also reported decreased grey matter volume in the same regions in young people with autism but increased white matter volume in regions containing limbic pathways. White matter differences have been reported in a voxel-based diffusion study, which found that children with autism have significant microstructural differences (e.g. reduced fractional anisotropy) in the anterior cingulum and medial temporal lobe (Barnea-Goraly et al., 2004). A recent tractography study showed that compared to healthy controls, adults with Asperger’s syndrome had a significantly higher number of streamlines in the cingulum bilaterally and a lower number of streamlines in the right uncinate (Pugliese et al., 2009). Together the post-mortem and in vivo studies suggest anatomical changes of the dorsal cingulum and uncinate fasciculus in autism spectrum disorder.
from “Atlas of the Human Brain Connections” . Catani, Thiebaut de Schotten – Oxford, 2012
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